HAPPY TO BRING TOGETHER THIS 130th MEETING OF IF GNASHNA ADVISORY COUNCIL ON AGING GNASHAL INSTITUTE ON AGING. I'M (INAUDIBLE). I'M GOING TO TRANSITION OVER TO -- (INAUDIBLE) >> WHILE MALI IS DOING THAT, -- MARIE IS DOING THAT, THIS VIDEO BEING VIDEOCAST. SMILE APPROPRIATELY. COMB YOUR HAIR. ALL RIGHT. >> RICHARD DOES OFFER HIS APOLOGIES, HE WAS ASKED TO PARTICIPATE IN THE WORLD ECONOMIC FORUM SO HE'S IN DABOS AT THIS TIME AND SENDS HIS REGARDS TO ALL IN HOMAGE TO RICHARD I CONSIDERED WEARING LIGHT BLUE SLEEVELESS SHIRT AND KHAKIS BUT THEY WERE IN THE CLEANERS. BUT RICHARD ALWAYS PROVIDES UPDATES ON BUDGET AND WHAT WE CAN TELL IS WE'RE IN A CONTINUING RESOLUTION THROUGH TO APRIL 28. SO THE CURRENT PRESIDENT HAD PROPOSED FOR FISCAL YEAR 17 WHICH STARTED OCTOBER 1 THAT WE HAVE A BUDGET FLAT TO FISCAL YEAR 16. WITH A CONTINUING RESOLUTION WE GENERALLY SPEND UP TO 90% OF WHAT IS AUTHORIZED THE PREVIOUS YEAR, THERE'S AN INAUGURATION ON FRIDAY AND WITH THE NEW PRESIDENT AND CONGRESS WE'LL SEE WHAT'S ALLOCATED FOR HIPPOAND OTHER GOVERNMENT A-- NIH AND OTHER GOVERNMENT AGENCIES, THE CONTINUING RESOLUTION GOES THROUGH TO APRIL 28th. WITH THE CONTINUING RESOLUTION HOWEVER THERE WAS ALSO SOMETHING CALLED THE 21st CENTURY CURES ACT, PASSED PRIOR TO THAT, AND IT AUTHORIZED SPENDING INCORPORATED TO THE RESOLUTION SO THE 21st CENTURY CURES ACT WAS PASSED BY THE HOUSE AND SENATE IN EARLY DECEMBER AND SIGNED INTO LAW BY PRESIDENT OBAMA DECEMBER 13 AND HAS A NUMBER OF PROVISIONS OF INTEREST TO US. FIRST OF ALL, FUNDING FOR A NUMBER OF INITIATIVES WITHIN NIH, SPECIFICALLY THE PRECISION MEDICINE INITIATIVE, THE BRAIN INITIATIVE, THE CANCER MOON SHOT, WHICH GOD RENAMED THE FULL BIDEN CANCER INITIATIVE, THE REGIONTIVE MEDICINE INITIATIVE. AND THIS KIND OF CRAZY PLOT YOU SEE HERE SHOWS HOW THE FUNDING IS ANTICIPATED OVER THE COURSE OF THE NEXT TEN YEARS THESE VARIOUS INITIATIVES, IT COMES FROM THE PREVENTIVE FUND AND STRATEGIC OIL RESERVES SO THE MONEY AVAILABLE IS VARIABLE YEAR-TO-YEAR. SO YOU SEE PRECISION MEDICINE INITIATIVE THE MONEY GOES UP IN 2019, DOWN IN 2021, GOES UP 2023 AND BACK DOWN IN 2026. SIMILARLY FOR THE BRAIN INITIATIVE, UP AND DOWN UP AND DOWN. UP HERE YOU SEE THE BIDEN INITIATIVE, UP TO ITS PEAK IN 2019 AND ENDS IN 2023. REGENERATIVE MEDICINE INITIATIVE ENDS IN 2020. IT WILL TAKE A LITTLE BIT OF CREATIVITY AND INNOVATION ON THE PART OF NIH STAFF TO MANAGE UP AND DOWNS, THEY WILL CERTAINLY DO THAT. AS MENTIONED, THE PROGRAM WITHIN THE # 1st CENTURY CURES ACT INCLUDES FUNDING FOR PRECISION MEDICINE INITIATIVE, THERE'S A CALL FOR NEXT GENERATION RESEARCH INITIATIVE THE ESTABLISHMENT OF OFFICE AND OFFICE OF NIH DIRECTOR TO ENSURE THE PIPELINE OF FUTURE SCIENTISTS, THERE'S A PROVISION TO RAISE NIH LOAN REPAYMENT PROGRAM FROM CURRENT $35,000 ANNUAL CAP TO $50,000. THERE IS A PRIME AUTHORITY WRITTEN INTO THAT LAW THAT ALLOWS NIH TO DO COMPETITION. THERE'S A NUMBER OF PROVISIONS THAT RELIEVE ADMINISTRATIVE BURDEN, NIH IS EXEMPTED FROM THE PAPERWORK REDUCTION ACT, PRIOR TO THIS EXEMPTION IN ORDER TO DO ANY SORT OF SURVEY NIH WOULD HAVE TO GET APPROVAL, SURVEY MORE THAN NINE INDIVIDUALS ENTITIES NIH WOULD HAVE TO GET APPROVAL FROM OFFICE OF MANAGEMENT AND BUDGET. THAT IS RELIEVED WITH THIS ACT. FOR RESEARCH PURPOSES. ADDITIONALLY, WE HAVE SINCE 2012 HAD RESTRICTIONS ON TRAVEL PROGRAM STAFF TO CONFERENCES, AND OTHER SCIENTIFIC ACTIVITIES. AND THAT WE ARE NOW EXEMPTED FROM THOSE RESTRICTIONS ALTHOUGH WE WILL ON AN ANNUAL BASIS REPORT ON WHAT TRAVEL IS DONE. FOR GRANTEES THE OFFICE OF MANAGEMENT AND BUDGET MUST ESTABLISH POLICY BOARD REVIEW TO LOOK AT REGULATIONS ACROSS FEDERAL AGENCIES, THE IDEA TO MAKE THINGS MORE EFFICIENT AND LESS CUMBERSOME. DEPARTMENT OF HEALTH AND HUMAN SERVICES, TO EXAMINE FINANCIAL CONFLICTS OF INTEREST UPON EXPENDITURE REPORTING. NIH MUST CONSIDER WAYS TO REDUCE THE BURDEN RELATED TO SUBCONTRACTS WITHIN GRANTS. VERY IMPORTANTLY FROM THE NATIONAL INSTITUTE ON AGING THERE'S NEW PROVISIONS WHICH REGARDS TO INCLUSION. I WILL REMIND YOU THAT OUR TAX MINORITY RESEARCH A COUPLE OF YEARS AGO EXPRESSED CONCERNS AN'T ADEQUACY OF OLDER ADULTS IN CLINICAL STUDY. AND THE 21st CENTURY CURES AMONG THINGS MENTIONED HAS BEEN RELATED TO AGE SO GOING DOWN THE LIST INCLUSION PROVISIONS IN THE 21st CENTURY CURES BILL CALLED FOR NIH TO ENSURE INCLUSION OF WOMEN, CHILDREN AND RACIAL AND ETHNIC MINORITIES CALLS TO APPROVE RESEARCH RELATED TO SEXUAL AND GENDER MINORITY POPULATIONS. AS YOU WILL HERE WHEN THE TASK FORCE MINORITY RESEARCH REPORT IS GIVEN THAT IS A NEWLY DESIGNATED SPECIAL POPULATION. FROM WE ARE TO ASSEMBLE THAT POPULATION CLINICAL RESEARCH WOMEN MINORITIES AND FOR THE FIRST TIME EMPHASIS ON AGE CATEGORIES. AND AS YOU SEE IN BOLD, THERE IS A PROVISION THAT REQUIRES THAT NIH DIRECTOR TO HOLD A WORKSHOP AND VERY SPECIFICALLY THE VERBIAGE IN THE LAW SAYS WITHIN 180 DAYS OF BILL HAVING BEEN FINED, THAT WITHIN 180 DAYS AFTER THAT, THE NIH DIRECTOR UPDATE POLICIES AS APPROPRIATE. GIVEN THAT WE HAVE BEEN ASKED TO GIVE TECHNICAL ASSISTANCE AT VARIOUS VERSIONS OF THE 21st CENTURY CURES BILL BEING DEVELOPED THERE'S A TRANS-NIH GROUP WORKING ON THIS SINCE OCTOBER. DR. (INAUDIBLE) WHO LEADS OFFICE OF PLANNING AND EVALUATION IS CO-CHAIRING WITH THE COLLEAGUE FROM THE DENTAL INSTITUTE, A PLANNING COMMITTEE FOR THIS WORKSHOP ACROSS THE LIFE SPAN. WE ARE ENENCOURAGED TO UTILIZE THE STUDY POPULATION. SO MORE ABOUT THIS REQUIRED WORKSHOP, WE'RE ENVISIONING IT WILL TAKE PLACE JUNE 1st TO 2ND AT NATCHER. PLANNED AREAS OF FOCUS WILL INCLUDE IMPACT OF EXCLUSION INCLUDING PEDIATRIC AND OLDER POPULATION, DESIGN ISSUE, EXPERTISE TO ENHANCE INCLUSION, NIH REPORTING REQUIREMENTS AND THE INTERSECTION OF AGE AND OTHER DEMOGRAPHIC VARIABLES SUCH AS RACE ETHNICITY AND NEXT STEPS TO SOLVING THE PROBLEM. IT'S NOT THE INTENT OF NIH TO ASK THE PSYCHOCOMMUNITY TO TELL US VERY SPECIFICALLY WHAT -- OF THE NIH COMMUNITY TO ASK SPECIFICALLY WHAT IS CHANGED BUT WHAT ARE THE BARRIERS TO THE INCLUSION OF PEDIATRIC AGE POPULATION AND OLDER POPULATIONS IN CLINICAL STUDIES AND WHAT ARE THE OPPORTUNITIES THAT WE MIGHT HAVE TO ENHANCE THEM. I THINK WE HAVE SHARED WITH YOU, I WANT TO REINFORCE THAT OVER THE LAST COUPLE OF YEARS THAT'S AN INCLUSION GOVERNANCE COMMITTEE, THE TRANS-NIH ANALYSIS OF INCLUSION OF OLDER ADULTS. IN PHASE 3 CLINICAL TRIALS THAT ADDRESS CONDITIONS PREVALENT IN OLDER POPULATIONS, TOP TEN CAUSE OF HOSPITALIZATIONS DISABILITY ADJUSTED LIFE YEARS, LED BY DR. SOMA AND HIS COLLEAGUES IN OUR PLANNING OFFICE. AND THAT ANALYSIS SUGGESTED OPPORTUNITIES FOR BETTER REPORTING AND BETTER INCLUSION. THE 21st CENTURY CURE CONSIST BILL ALSO HAD PROVISIONS WITH REGARD TO DATA ACCESS AND PRIVACY, IT EXEMPTS CERTAIN INFORMATION FROM FREEDOM OF INFORMATION REQUESTS, IT REQUIRES ISSUANCE OF CERTIFICATES OF CONFIDENTIALITY AND ENHANCES PROE THE. IT AUTHORIZE IT IS NIH DIRECTOR TO REQUIRE FUNDING TO SHARE DATA, AS DR. BARR MENTIONED TO COUNCIL YESTERDAY. HERETOFORE STRONGLY ENCOURAGE LOTS OF CAJOLING NOW, THE AUTHORITY TO REQUIRE THE SHARING OF DATA, EXACTLY HOW THAT IS WORKING, IS STILL BEING WORKED OUT. NIH STRATEGIC PLAN EVERY FIVE YEARS, FORTUNATELY ANTICIPATING THIS WE DID A STRATEGIC PLAN LAST YEAR AT THE URL LISTED THERE. SO 2020 NEEDS TO BE REVISED. MORE EMPHASIS ON REPRODUCIBILITY WITH THE WORKING GROUP FOCUSING ON THAT. SO ANTICIPATING YOUR QUESTION, WHAT IS THE NEXT STEPS. HOW IS THIS GOING TO ROLE OUT? THERE ARE LOTS OF DIFFERENT PROVISIONS THAT YOU SAW, LOT OF DIFFERENT TIME LINES WITH IMPLEMENTATION, THOSE PROVISIONS AND THERE'S BEEN LEGISLATION -- LEGISLATIVE IMPLEMENTATION WORK GROUP DEVELOPED BY OFFICE OF NIH DIRECTOR THAT'S LED BY VARIOUS INSTITUTE DIRECTORS AND PEOPLE FROM THE DIRECTORS OFFICE, NEEDING TO REVIEW THE STATUTE AND TO FIND IMPLEMENTATION PLANS, THE APPROPRIATE INSTITUTE OR OFFICE OF DIRECTOR OFFICE, THOSE GROUPS WILL THEN PROVIDE A PLAN FOR HOW WE MIGHT IMPLEMENT THINGS INTO THE WORK GROUP BUT THEN ULTIMATELY GET SUBMITTED TO THE NIH DIRECTOR. GIVEN THE SHORT TIME LINE WE'RE ON FOR THE INCLUSION OF LIFE SPAN WORKSHOP THERE'S ALREADY BEEN CONVERSATION WITH DIRECTOR'S OFFICE HOW BEST TO IMPLEMENT THINGS AND WHETHER WE WILL BE NEEDING THE INTENT OF THE STATUTE. -- MEETING THE INTENT OF THE STATUTE. OTHER UPDATES. ALWAYS NICE TO SEE OUR RESEARCH IS APPRECIATED BY MORE THAN JUST THE NATIONAL INSTITUTE ON AGING. THREE NIH SUPPORTED FINDINGS WERE AMONG THE MOST TALKED ABOUT ARTICLES IN THE AMERICAN MEDICAL ASSOCIATION OR JAMA NEUROLOGY IN 2016. THOSE ARE ASSOCIATION BETWEEN INCOME AND LIFE EXPECTANCY IN UNITED STATES IN JAMA, COMING OUT OF DAVID CUPPERS GROUP, THE EFFECT OF CRANBERRY ON EFFECT OF OLDER WOMEN IN NURSING HOLMES H GERIATRICIAN, VERY IMPORTANT ISSUE AND THE READERS OF JAMA THOUGHT THAT WAS THE CASE COMING OUT OF YALE COVER CENTER. IN JAMA NEUROLOGY SEX AND RACE DIFFERENCES IN ASSOCIATION BETWEEN STATIN USE AND INCIDENCE OF ALZHEIMER'S DISEASE, IT'S NICE TO SEE RESEARCH IS SO NICELY DISSEMINATED. OTHER THINGS HOPEFULLY THOSE OF YOU INVOLVED WITH DOING CLINICAL TRIALS HAVE BEEN AWARE THERE'S BEEN CLINICAL TRIAL POLICY CHANGES, THERE'S A LONG JOURNEY FROM IDEA TO THE RESULT OF CLINICAL TRIAL IN CHANGES JUST ABOUT EVERY STEP. THE STEP BETWEEN THE IDEA AND APPLICATION, THERE'S NOW REQUIREMENT FOR GOOD CLINICAL PRACTICE TRAINING, EVERY INVOLVED WITH CLINICAL TRIALS WHETHER ADMINISTRATION IMPLEMENTATION, EVEN PEOPLE LIKE THE NIA DIRECTOR, NIA DEPUTY DIRECTOR HAD TO GO THROUGH GOOD CLINICAL PRACTICE TRAINING BY JANUARY 1 TO MAKE SURE WE ARE DOING THE RIGHT THING. THEN YOU GO TO APPLICATION AND BETWEEN THE APPLICATION AND APPLICATION REVIEW, THERE IS NOW EXPECTATION AT NIH THAT THERE WILL BE A STANDARD -- THERE WILL BE A FUNDING OPPORTUNITY ANNOUNCEMENT FOR SPECIFIC CLINICAL TRIALS THAT THERE WILL NO LONGER BE CLINICAL TRIALS I THINK IS ACTUALLY OFFICIALLY EMBEDDED, WILL BE IMPLEMENTED LATER THIS FISCAL YEAR BUT THE EXPECTATION IS THAT CLINICAL TRIALS WILL NO LONGER BE EMBEDDED IN THE -- THERE WILL BE SPECIFIC FOA FOR CLINICAL TRIAL TO ALLOW TRACKING OF OUTCOMES TO MAKE SURE THERE'S CERTAIN STANDARDIZED ELEMENTS AND STANDARDIZED REVIEW SO THAT WE DO A MUCH BETTER JOB STEWARDSHIP OF OUR CLINICAL TRIAL. BETWEEN FUNDING AND IRB REVIEW THERE'S NOW THE PROVISION OF -- BY NIH FOR SINGLE IRB REVIEW OF PROJECTS WITH MULTIPLE SITES WITHIN THE UNITED STATES. THERE'S THE EXPECTATION OR THE STRONG ENCOURAGEMENT OF THE USE OF PROTOCOL TEMPLATE FOR STUDIES THAT MAY END UP NEEDING FDA REVIEW, THIS IS -- THIS TEMPLATE IS JOINTLY BETWEEN FDA AND NIH. THERE'S NEW EXPECTATIONS AND REQUIREMENTS IN TERMS OF CLINICALTRIALS.GOV REGISTRATION, EXPECTATION THAT IN THAT THE TRIAL WILL BE REGISTERED WITHIN 21 DAYS WITHIN RECRUITMENT OF THE FIRST SUBJECT EXPECTATION OF THE PROVISION OF RESULTS TO CLINICAL TRIALS.GOV AND EXPECTATION THAT NIH MAY WITHHOLD FUNDING TO THAT INSTITUTION IF THAT REPORTING IS NOT PUT IN PLACE OR NOT ACCOMPLISHED. LOTS OF CHANGES WITH THE GOAL OF MAKING SURE WE'RE BEING GOOD STEWARTS AND MAKING SURE THE QUALITY OF THE STUDY IS GOOD. AS YOU MAY REMEMBER AT THE LAST COUNCIL WE HAD NUMBER OF OLE THAT WAS CLEARED IN ANTICIPATION THIS FISCAL YEAR. IS AND WE ARE HAPPY TO REPORT THE CONCEPTS NOW BECOME FUNDING OPPORTUNITY ANNOUNCEMENTS, I BELIEVE DR. BARR BELONGED TO THAT, THAT WILL BE COMING OUT THE NEXT COUPLE OF HOURS AND HOPEFULLY ALL OF YOU FOUND THAT TO BE A BENEFICIAL PROCESS, PARTICULARLY THE FACT THAT WE POSTED THE CONCEPTS AS SOON AS COUNCIL IS OVER. WE GOT SO MUCH IN THE WAY OF POSITIVE FEEDBACK ABOUT THE IDEAS OF CONCEPTS HAVING BEEN POSTED THAT WE'LL MAKE MAKE IT A RADIOTEEN SETTING. WE WILL HEAR THE NUMBER OF CONCEPTS AS WELL SO THOSE CONCEPTS THAT ARE APPROVED WE WILL POST THEM, YOU WILL BE ABLE TO FIND IT AT THIS URL. I TESTED IT THIS MORNING, IF YOU JUST DO CONCEPTSEN OUR WEBSITE, IT WILL BRING UP THAT PAGE, THERE'S NOTHING THERE YET THAT IS AN OPPORTUNITY TO GET A CLEAR SENSE OF THE THOUGHTS BEHIND THINGS DISCUSSED HERE AT COUNCIL. HOPEFULLY YOU HAVE ALSO FOUND ON OUR WEBSITE, THE FUNDING OPPORTUNITY ANNOUNCEMENTS, IS AN OPPORTUNITY GENERAL FUNDING OPPORTUNITY ANNOUNCEMENTS OR YOU CAN DO SPECIFICALLY JUST A DEANNOUNCEMENT SO HOPEFULLY THAT'S HELPFUL TO EVERYONE. WHILE TALKING ALZHEIMER'S DISEASE THERE'S A COUPLE OF DATES COMING UP THAT'S IMPORTANT TO KNOW. THERE'S A RESEARCH SUMMIT ON NIH CAMPUS OCTOBER 16th AND 17th. THERE'S A THIRD OVERALL ALZHEIMER'S DISEASE SUMMIT COMING UP MARCH 1, 2 BUT ON THE NIH CAMPUS, STAY TUNED FOR THE NOTICE OF REGISTRATION BEING OPEN FOR EACH OF THESE. THEN FINALLY, THERE ARE A NUMBER OF THINGS THAT OCCURRED AS YOU MIGHT ANTICIPATE WITH THE ADMINISTRATION IN TERMS OF NOMINATIONS. WE HAVE REPRESENTATIVES TOM PRICE NOMINATED TO BE THE SECRETARY OF HEALTH AND HUMAN DEPARTMENT OF HEALTH AND HUMAN SERVICES, HE IS A PHYSICIAN TRAINED AT UNIVERSITY OF MICHIGAN. HE DID RESIDENCY TRAINING AND ORTHOPEDIC SURGEON AT EMORY UNIVERSITY. CHAIR MAN ON THE COMMITTEE OF BUDGET AND BOTH CONGRESSIONAL HEALTHCARE CAUCUS AND DOCTOR'S CAUCUS. YOU MAY HAVE HEARD SOME OF THE QUESTIONS POSED TO HIM AS HE'S GONE THROUGH THE SERIES IT IS PAST WEEK THE NOMINEE CENTER FOR MEDICARE MEDICAID SERVICES IS (INDISCERNIBLE) PRESIDENT AND FOUNDER OF SBC HEALTH POLICY CONSULTING COMPANY AND SHE WORKED WITH GOVERNOR MIKE PENCE TO DESIGN INDIANA MEDICAID EXPANSION PLAN. WE DON'T YET HAVE WORD AS TO WHO THE NOMINEE WILL BE FOR NIH DIRECTOR. SO STAY TUNED. AFTER WE -- AFTER I ANSWERED WHATEVER QUESTIONS YOU MIGHT HAVE WE MIGHT ALSO INTRODUCE A NUMBER OF NEW STAFF WHO ARE HIGH VALUE INDIVIDUALS FOR US HERE AT NIA. I'LL END AT THAT POINT AND ENTERTAIN ANY QUESTIONS YOU MIGHT HAVE. >> DR. CUMMINS. FOR INITIATIVES LIKE PRECISION MEDICINE INITIATIVE, I WANT TO FIND WHAT DO YOU THINK THE IMPACT IS OF THAT FUNDING ON OTHER FUNDING FOR VIOLATETOR INITIATED RESEARCH, IS IT ALL OF THAT SPECIAL FUNDING ON TOP OF THE INCREASES IN OTHER CLIENTS? >> THAT IS ALL SPECIAL FUND, IT COMES FROM THE PREVENTION FUND AND FROM STRATEGIC OIL RESERVES. SO AS YOU SAW ALL OF IT ENDS IN TEN YEARS, SO THAT IS SEPARATE FROM THE SPECIFIC ALLOCATION FOR NIH. >> WHILE YOU'RE THINKING OF THE QUESTIONS I'M GOING TO BRING UP ANOTHER ITEM WHICH IS THAT I POSTED THE ECLIPSE FOR USE ITEMS ON NIA OR NIA SUPPORTED RESEARCH ON THE CURRENT COUNCIL TAB LAST NIGHT. IT'S RIGHT AT THE TOP OF THE CURRENT COUNCIL TAB. IT'S A LARGE PDF FILE. THAT COVERS THE NEWS ON NIA BETWEEN SEPTEMBER AND DECEMBER, SO IF YOU WANT TO BROWSE THAT YOU CAN BROWSE THAT, THERE ARE QUITE A LOT OF NEWS REPORTS ON OUR RESEARCH. TOO MANY TO MENTION FRANKLY. OTHER QUESTIONS FOR DR. BERNARD? >> IF YOU HAVE NO QUESTIONS FOR ME, WHAT I WANTED I WOULD LIKE TO DO IS ASK EACH OF THE DIVISION DIRECTORS TO PERHAPS HAVE A SEAT AT THE TABLE AND BRIEFEDLY INTRODUCE NAME, AND ROLE WITHIN YOUR DIVISION. NEW STAFF MEMBERS THAT YOU HAVE BECAUSE IT'S BEEN REALLY A WONDERFUL FEW WEEKS IN TERMS OF BRINGING ON NEW MEMBERS OF THE FAMILY. >> I DON'T SEE HER BUT I WOULD LIKE TO INTRODUCE EVERYBODY TO CAN DIS(INAUDIBLE) ASSISTANT PROFESSOR WITH EXPERTISE ON (INAUDIBLE) SCIENCE. SHE WILL BE JOINING THE IMMUNOLOGY BRANCH IN CHARGE OF STEM CELLS, REGENERATIVE MEDICINE AND AGING PHYSIOLOGY. IS CANDICE HERE? SHE'S NOT HERE YET. YOU'LL SEE HER LATER. >> OUR DIVISION HAD A LARGE NUMBER OF PHYSICIANS THAT NEED TO BE FILLED OVER THE YEARS SO I WILL ASK THE BRANCH CHIEFS TO INTRODUCE PEOPLE, AND THEIR BRANCHES. FIRST I WOULD LIKE TO INTRODUCE DEPUTY DIRECTOR DANA PLOOD, SHE COMES FROM CENTER FOR SCIENTIFIC REVIEW AT NIH, HE WAS RECENTLY DEPUTY DIRECTOR DIVISION OF RECEIPT AND REFERRAL THERE. BEFORE THAT ACTING DIRECTOR OF DIVISION OF AIDS, BEHAVIORAL AND POPULATION SCIENCES. AND CHIEF OF THE BIOBEHAVIORAL AND BEHAVIORAL PROCESSES INTEGRATED REVIEW GROUPS SO YOU CAN SEE HE'S BEEN INVOLVED IN OUR FUNDED RESEARCH FOR IMPORTANT WAY AND QUITE A WHILE. BEFORE JOINING NIH DANA WAS ASSOCIATE PROFESSOR OF DEVELOPMENTAL PSYCHOLOGY AT THE UNIVERSITY OF MARYLAND COLLEGE PARK ASSOCIATE CHAIR OF GRADUATE STUDIES FOR THAT DEPARTMENT. HE HAS PRIVATE SECTOR EXPERIENCE IN SBIR GRANTEE HAVING SERVED AS VICE PRESIDENT FOR GERONTOLOGICAL RESEARCH FOR COMPACT INCORPORATED, Ph.D. IN PSYCHOLOGY WAS AWARDED BY SYRACUSE UNIVERSITY. ROXANNE SIMPLE, I'M GOING IN ORDER -- ALPHABETIC ORDER HERE, EXTRAMURAL RESEARCH ASSISTANT SINCE JUNE BUT WASN'T INTRODUCED AT THE SEPTEMBER COUNCIL. BEFORE JOINING US SHE WAS BUILDING AND ADMINISTRATIVE COORDINATOR FOR A PHYSICIAN PRACTICE AND SHE MANAGED RADIOLOGY DEPARTMENTS WITH QUANTICO IN PENSACOLA AND IN ITLY FOR THE U.S. NAVY. SHE HAS ASSOCIATE DEGREE FROM GEORGE WASHINGTON UNIVERSITY AND PROFESSIONAL CERTIFICATES IN FIELDS AND ELECTRONIC HEALTH RECORDS QUALITY IMPROVEMENT AND LEADERSHIP ADS A NAVY VETERAN. (INDISCERNIBLE) IS PROGRAM SPECIALIST AT THE JOB FORMERLY CALLED THE EXTRAMURAL PROGRAM OFFICE MANAGER, HAS BEEN WORKING FOR US UNDER CONTRACT FOR SEVERAL MONTHS AND IS NOW HIRED IN A REGULAR POSITION. BEFORE SHE WAS ASSISTANT DIRECTOR IN CHARGE OF OPERATIONS FOR PHOENIX ONE SERVICES, A SMALL GOVERNMENT CONTRACTOR AND SENIOR ADMINISTRATIVE ASSISTANT FOR THE GABY ALLIANCE, COMPLEX INTERNATIONAL ORGANIZATION THAT THAT FOSTERS VACCINE INITIATIVES AND AN EVENT PLANNING CONSULTANT, SHE'S ATTENDED SAINT PAUL'S COLLEGE AND HAS CERTIFICATES IN ADMINISTRATION. WE'RE DELIGHTED TO HAVE ALL THREE. GEORGE ANN WILL YOU MENTION THE PEOPLE AT YOUR BRANCH? >> GOOD MORNING, HAPPY TO INTRODUCE TWO NEW HSAs AND BSR POPULATION SOCIAL PROCESSES BRANCH, FIRST DR. AMELIA KERKAR FROM EYE I STATE UNIVERSITY ASSISTANT PROFESSOR HUMAN DEVELOPMENT AND FAMILY STUDIES. PRIOR TO THAT AMELIA WAS A NIH POST DOC FELLOW AT THE POPULATION STUDY CENTER UNIVERSITY OF MICHIGAN, SHE'S USED SEVERAL OF THE NIA DATA RESOURCES THAT WE SUPPORT WITH HER RESEARCH HAD BEEN GENERALLY INTERNATIONAL INTERGENERATIONAL SUPPORT MARRIAGE AND FINANCIAL SECURITY OF THE ELDERLY AND PSYCHOSOCIAL FACTORS AND HEALTH ACROSS THE LIFE COURSE. HER Ph.D. WAS AWARDED IN SOCIOLOGY BY UNIVERSITY OF WISCONSIN MADISON AND SHE DID A -- I MENTIONED THE POST-DOC UNIVERSITY OF MICHIGAN SO WE'RE THRILLED SHE'S JOINED SHE WILL BE MANAGING OUR PRIMARILY PORTFOLIOS IN DEMOGRAPHY AND SOCIAL EPIDEMIOLOGY ON AGING. NEXT DR. ELENA JOINED LAST WEEK AS A NEW HSA AND THE POPULATION SOCIAL PROCESSES BRANCH. SHE WILL BE WORKING ON PROSPECTS WITH THE GOALS OF ALZHEIMER'S PLAN OF ACTION AND WILL HAVE A PORTFOLIO MOSTLY RELATED TO LONG TERM SUPPORTS AND SERVICES FOR THE ELDERLY. SHE JUST CAME JUST JOINED US FROM ANOTHER COMPONENT OF HHS, THE U.S. ADMINISTRATION FOR COMMUNITY LIVING WHERE SHE HAD A WIDE VARIETY OF RESPONSIBILITIES RELATED TO PROGRAMS, EVALUATION AND DATA COLLECTION ON AGING AND DISABILITY BEFORE JOINING ADMINISTRATION FOR COMMUNITY LIVING SHE WAS STAFF DIRECTOR FOR THE INTERAGENCY FORUM ON AGING RELATED STATISTICS. HER Ph.D. IS IN SOCIOLOGY AWARDED BY UNIVERSITY OF MARYLAND AND ELENA DID A POST DOC AT UNIVERSITY OF MARYLAND. SO WE'RE THRILLED. >> FINAL TWO NEW STAFF ADMISSIONS IN BEHAVIORAL AND SOCIAL RESEARCH IN INDIVIDUAL PROCESSES BRANCH WE HIRED TWO NEW PROGRAM ANALYSTS, (INDISCERNIBLE) WHO I DON'T THINK IS HERE YET JOINED US AS OUR RESEARCH PROGRAM ANALYST AND SUPPORT THE ENTIRE DIVISION ACTIVITIES RELATED TO ALZHEIMERS DISEASE BATCH ALREADY IN SCIENCE FROM UNIVERSITY OF GHANA AND NPH IN PUBLIC HEALTH FROM UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER. HE'S A U.S. ARMY VETERAN WORKING AS EPIDEMIOLOGIST AND HEALTH SPECIALIST AT THE DEFENSE HEALTH HEADQUARTERS AGENCY, ACCOUNT OF NAVY, ARMY AND VETERANS AFFAIRS. SECOND WE HAVE HIRED AS A FEDERAL EMPLOYEE MS. LAURA MAJOR WHO IS HERE, WHO WORKED WITH US FOR A CONTRACTOR FOR MOST OF THE LAST YEAR BUT JOINED OFFICIALLY AS PERMANENT EMPLOYEE OCTOBER. LAURA RECEIVED BA IN ANTHROPOLOGY AND PSYCHOLOGY FROM DICKINSON COLLEGE AND NPH HEALTH BEHAVIOR NORTH CAROLINA CHAPEL HILL, PRIOR TOP COMING TO NIA LAURA WORKED AS WESTAT ON RESEARCH OPERATIONS NATIONAL HEALTH AND NUTRITION AND EXAMINATION SURVEY, SO WE'RE SUPPORTING ACTIVITIES IN THIS DIVISION. [APPLAUSE] >> FOR THE DIVISION OF NEUROSCIENCES AND -- I'LL INTRODUCE ALL OUR NEW MEMBERS OF THE FAMILY AND ALSO WE HAVE BRANCH CHIEFS TO MAKE MORE -- FASTER -- FOR THE BRANCH BEHAVIORAL SYSTEMS NEUROSCIENTIST, MOLLY'S BRANCH WE HAVE TWO DISTINGUISHED NEW MEMBERS, ONE IS AUTUMN STEINMETZ. SO AUTUMN IS JOINING US FROM NYU, HE OBTAINED HIS Ph.D. IN PSYCHOLOGY FROM THE UNIVERSITY OF IOWA, DOCTORAL FELLOWSHIP AT NYU WHERE HE WORKED ON POST TRAUMATIC STRESS DISORDER AND COGNITIVE DECLINE RELATED TO AGING. ALSO JOINING MOLLY'S BRANCH BEHAVIORAL SYSTEMS AND NEUROSCIENTIST BRANCH, WE HAVE LUCY ROBERTS HERE, LUCY JOINED A NIND PROGRAM RECENTLY, SHE WAS ON DETAIL WITH US, BUT SHE WAS PREVIOUSLY SERVING AS DIRECTOR OF DIVISION OF PLANNING EVALUATION AND ANALYSIS AND PRIOR TO THAT SHE WAS ON DETAIL WITH US, HAD ACTIVITIES INCLUDED PROVIDING PROGRAMMING OVERSIGHT FOR THE BRANCH AND ORGANIZING A NUMBER OF MEETINGS INCLUDING OPTOGENETICS MEETINGS WE HAVE PRIOR TO THAT, SHE ALSO HAD AN EXTENSIVE PORTFOLIO IN STRATEGIC INITIATIVE AS OFFICE OF DIRECTOR AND SERVICING IN THE SCIENTIFIC REVIEW. LUCY OBTAINED HER Ph.D. IN SOCIOLOGY FROM THE UNIVERSITY OF MARYLAND COLLEGE PARK. THEN FOR OUR DIVISION OF NEUROBIOLOGY OF AGE -- BRANCH OF NEUROBIOLOGY OF AGING, THAT IS BRANCH, WE HAVE AMANDA DEBATISTA. AND AMANDA RECENTLY JOINED US, SHE WAS PROFESSOR OF NEUROSCIENCE AND HE RESEARCH FOCUSED ON ALZHEIMER'S DISEASE IN PARTICULAR APOE AND RISK FOR ALZHEIMER'S DISEASE WORKING WITH (INAUDIBLE) PRIOR TO JOINING NIH HEARSAY SERVED AS ASSOCIATE REVIEWER AND WORK AT PLUS 1 AND ALSO JOINING THE BRANCH OF NEUROBIOLOGY OF AGING WITH BRAD AND WE HAVE LISA (INAUDIBLE) AS WELL, THANK YOU. AND LISA WAS A SCIENTIFIC PROGRAM MANAGER AT THE VA ADMINISTRATION HEALTH ADMINISTRATION. RESEARCH TO US CANNED ON CLINICAL RESEARCH PROGRAMS AN AGING, NEUROLOGICAL DISORDERS INCLUDING ALZHEIMERS DISEASE AND RELATED DEMENTIA. AS PART OF FUNCTION OF BA SHE HAS WORK AS LIAISON WITH SEVERAL GOVERNMENT AND NON-GOVERNMENTAL AGENCIES. SHE PREVIOUSLY PARTICIPATED AT THE NIH RESEARCH SUMMIT, WITH NINDS SUMMIT AND PRIOR TO THAT ASSOCIATE PROFESSOR AT THE UNIVERSITY OF ROCHESTER. WITH A FOCUS OF HER RESEARCH ON NEUROTOXICOLOGY AND NEUROINFLAMMATION. THEN WE HAVE NEW FOLKS JOINING US WITH THE BRANCH DEMENTIA BRANCH, THAT IS RYAN'S BRANCH AND WE HAVE KRISTIN SMITH HERE. AND KRISTIN RECEIVED A Ph.D. IN GERONTOLOGY FROM THE UNIVERSITY OF MARYLAND AND BALTIMORE AND HER RESEARCH WAS FOCUSED ON EXPLORING OPPORTUNITIES TO IMPROVE QUALITY OF LIFE FOR VARIOUS GROUPS OF AGING ADULTS WITH DIVERSE SOCIAL HISTORIES, PRIOR TO JOINING US SHE WORK AS A GRAD STUDENT AT THE UNIVERSITY OF MARYLAND DEPARTMENT OF EPIDEMIOLOGY AND PUBLIC HEALTH AND HAS PREVIOUSLY DONE RESEARCH AT THE DEPARTMENT OF HEALTH AND HYGIENE. WE HAVE ALSO WITH DEMENTIA BRANCH WE HAVE AUBURN MCELVIE. INTRODUCE YOU ALREADY,. AND I WAS INTRODUCING ALVIN, ALVIN HAS A Ph.D. IN BIOMEDICAL RESEARCH AT THE UNIVERSITY OF SOUTH CAROLINA AND DATA POST-DOCTORAL FELLOWSHIP AT JOHNS HOPKINS. HIS RESEARCH INTO THE ROLE OF INFLAMMATORY SYSTEM AND INFLAMMATORY MARKERS AND CHRONIC PAIN IN DIFFERENT MODELS INCLUDING PSYCHOSOCIAL AND ANEMIA AND SPINAL CORD INJURY. HE ALSO SERVE AS A REVIEW SPECIALIST AT TECHNICAL RESOURCES INTERNATIONAL, A PRIVATE FIRM WHERE HE FUNCTIONS INCLUDING EVALUATING SCIENTIFIC SAFETY DOCUMENTS RELATED TO CLINICAL TRIALS. AT THE -- WE HAVE KRISTINA LYNDON, KRISTINA COMPLETED HER POST-DOCTORAL FELLOWSHIP AT NINDS WITH (INDISCERNIBLE) WHERE RESEARCH WAS FOCUSED ON INVESTIGATING ROLE OF AGING ON NEURODEGENERATIVE DISORDERS, DID WORK ON DROSOPHILA AND MODELS OF ALZHEIMER'S DISEASE AND SHE CAME TO NIH IN PARTICULAR TO NIMH TO THE DIVISION OF TRANSLATIONAL RESEARCH WHERE SHE JOINED AS PROGRAM OFFICER ON THE PORTFOLIO NEUROINFLAMMATION AND CLINICAL RESEARCH. MORE RECENTLY KRISTINA WILL BE JOINING US AS I SAID LORI'S BRANCH WORKING ON CLINICAL TRIALS, SHE OBTAINED HER Ph.D. IN GENERAL EXPERIMENTAL PSYCHOLOGY AND BEHAVIORAL NEUROSCIENCES AT TEXAS CHRISTIAN UNIVERSITY. ALSO ON THE DEMENTIA BRANCH YOU HAVE LOU, PROBABLY SOME OF YOU KNOW FROM CSR AND AS I MENTIONED SHE'S IN THE SCIENTIFIC REVIEW OFFICE, CENTER FOR SCIENTIFIC REVIEW, MANAGING SCIENTIFIC REVIEW ON NEUROSCIENCES ON AGING SECTION. PRIOR TO THAT SHE WAS TENURE ASSOCIATE PROFESSOR AT UNIVERSITY OF MARYLAND IN BALTIMORE. SHE RECEIVED HER Ph.D. IN NEUROSCIENCES PHARMACOLOGY AT STATE UNIVERSITY OF NEW YORK IN SYRACUSE. AND CONDUCTED POST-DOCTORAL FELLOWSHIP AT MIT, HARVARD MEDICAL CENTER. FINALLY WE HAVE GENE -- GENE RECENTLY JOINED NIH, THE DIVISION OF NEUROSCIENCES, GENE IS WORKING DIRECTLY WITH ME, HELPING ME WITH ALL THE PLANNING AND ALL THE ANALYSIS AND ASSESSMENT THAT IS REQUIRED NOW WE'RE EXPANDING. SHE HAS A Ph.D. ON WORK ON LABORATORY AND CELLULAR DEVELOPMENTAL BIOLOGY HERE AT NIH. WHERE SHE ALSO DID WORK ON MOLECULAR ENDOCRINOLOGY AND DEVELOPMENT, SHE LATER BECAME TASKFORCE MEETINGWEPOINTED MILESTONES PROGRAM STAFF IN OUR DIVISION NEUROSCIENCE AND BEHAVIORAL SOCIAL RESEARCH. IN TERMS OF THE BROADER QUESTION OF INCLUSION IN OLDER ADULTS AND HOW INCLUSION OR EXCLUSION OF OLDER ADULTS MAY IMPACT UPON UNDER-REPRESENTED MINORITY POPULATION, IS AN ISSUE THAT'S BEEN RAIDED WITH THE PLANNING WORKSHOP INCLUSION ACROSS THE LIFE SPAN AND OUR HEROES IN THE PLANNING OFFICE UNDER DR. SOMA'S LEADERSHIP HAS BEGUN NAIL SEIZE OF TRANS-NIH PORTFOLIO TO SEE HOW WE DO ALONG THOSE LINES. PRELIMINARILY I CAN SAY AGAIN THERE ARE SOME OPPORTUNITIES FOR BETTER REPORTING, IT WILL BE A POINT OF DISCUSSION AT THE JUNE 2ND WORKSHOP. >> THANK YOU. WE'LL MOVE TO THE REPORT OF THE WORKING GROUP PROGRAM NOW WITH DR. CRIMMINS. >> THANK YOU. FIRST ITEM WE'RE GOING TO TALK ABOUT IS THE RECOMMENDATIONS FROM CTEP AND THAT WILL BE DONE BY ROBIN BARR. >> QUICKLY, THE CTEP ACCOUNT CLINICAL TRIAL ANALYSIS SUBGROUP COUNCIL REPORTED TO THE WORKING GROUP SOMEONE PROPOSED TRIAL TO NURSING HOMES TO REDUCE INFECTIONS AND SECONDARY HOSPITALIZATION. THE THEY REPORTED A VERY IMPORTANT TOPIC BUT THEY FELT THE PROPOSAL WAS PRELIMINARY, TOO PRELIMINARY AND THEY RECOMMENDED THE PEOPLE REVISE IT AND COME BACK WITH MORE PRELIMINARY DATA AND ANSWER TO QUESTIONS THEY RAISED ABOUT THE PROPOSAL WORKING GROUP AGREED WITH THAT ASSESSMENT. UNLESS Q. IS OBJECTION TO THE WORKING GROUP PROPOSAL, WE'LL TAKE THAT ASSESSMENT AND MOVE ON WITH IT. ALL RIGHT. >> ANY QUESTIONS FOR ROBIN? ALL RIGHT. WE WILL MOVE ON NOW TO THE CONCEPTS THAT WERE DISCUSSED AT SOME LENGTH YESTERDAY BY THIS GROUP. AND WE WILL REPORT ON THE ENDORSED -- CONCEPTS THAT WERE ENDORSED BY THE COUNCIL. THE FIRST ONE IS NOVEL MECHANISMS OF NON-AUTONOMOUS SIGNALS IN AGING AND LONGEVITY. TOM RANDO WILL REPORT ON THAT. >> THIS IS A PROPOSAL TO SET ASIDE FUNDS FOR RESEARCH IN GENERAL AREA OF NON-CELL AUTONOMOUS AGING WHICH IS THE CONCEPT THAT THERE'S SECRETED FACTORS THAT LOCALLY WITHIN TISSUE OR SYSTEMICALLY ACROSS THE BODY TO PROMOTE TISSUE AGING, THIS COMES FROM A CONVERGENCE OF VARIETY OF STIFF AREAS OF RESEARCH IN THE BIOLOGY OF AGING BUT NOW KIND OF EXTENDING THAT TO ANOTHER LEVEL, LOOKING AT SOME OF THESE MEDIATORS IDENTIFIED LOOKING FOR OTHER MEDIATORS LOOKING FOR TISSUES OF ORIGIN, FOR EFFECTS ON CELLS IN PARTICULAR, TRYING TO FIND COMMON MECHANISMS THAT MAYBE AT PLAY FROM SECRETED FACTORS THAT MAYBE DRIVING AND MECHANISMS OF DRIVING THE BIOLOGY OF AGING SO THIS WAS CONSIDERED TO BE HIGH IMPORTANCE, HIGH RELEVANCE, AND WAS UNANIMOUSLY SUPPORTED. >> THANK YOU ? I QUESTIONS FOR TOM? NEXT CONCEPT IS EFFECTS OF AGING ON HEMATOPOIESIS AND TOM RANDO WILL REPORT THAT. >> SET ASIDE FUNDS TO SUPPORT THE GENERAL AREA OF AGING IN HAT MAP SYSTEM, ASPECTS OF HEALTH OF OLDER PEOPLE RELATE TO HEMATOLOGIC ABNORMALITIES AND TRY TO UNDERSTAND THAT BETTER, I IT'S A VERY ACTIVE AREA OF RESEARCH LOOKING AT HOW HEMATOPOIESIS CHANGES WITH AGE BUT REALLY STILL A LOT TO BE LEARNED ABOUT HOW THAT AFFECTS BOTH IMMUNE FUNCTION AS WELL AS ISSUES LIKE DIVERSITY OF THE CELLS IN THE BLOOD AND PROPENSITY OF THOSE CELLS TO UNDERGO MALIGNANT TRANSFORMATION TO LEAD TO CANCERS OF THE ELDERLY IN THE BLOOD. THIS WAS CONSIDERED PA HIGH IMPORTANCE AND UNANIMOUSLY SUPPORTED. >> THANK YOU. ANY QUESTIONS? ALL RIGHT. THE THIRD CONCEPT, DEVELOPMENT AND COMMERCIAL AVAILABILITY OF CELL BASED TESTS FOR AGE RELATED CHANGES IN RESILIENCIES, PHYSICAL STRESSORS. JIM KIRKLAND WILL PRESENT THAT DOG SEPTEMBER. >> THIS IS AN -- CONCEPT. >> THIS IS AN INITIATIVE TO SUPPORT APPLICATIONS FROM SMALL COMPANIES OR ACADEMICS WORKING WITH SMALL COMPANIES TO DEVELOP CELL AND BIOSPECIMEN BASED ASSAYS WHO WHO LOOK FOR RESILIENCE THAT, IS CAPACITY TO RESPOND TO PERTURBATIONS. THESE TESTS WOULD BE APPLICATION IN CLINICAL TRIALS OF INTERVENTIONS ANDS ARE AS A DIAGNOSTIC TO PREDICT RESPONSE TO THINGS SUCH AS CHEMOTHERAPY OR SURGERY. THE GOAL IS TO DEVELOP SUCH TESTS TO THE POINT THEY COULD BE USED, THEY COULD BE USED IN THOSE TRIALS THROUGH COMMERCIAL DEVELOPMENT. THERE WAS GENERAL SUPPORT FOR THIS, THERE WAS A FEELING THE APPLICANT POOL MAYBE SMALL AND IF THAT'S THE CASE, THIS MIGHT BE EXPANDED TO OTHER GRANT MECHANISMS AS WELL. THIS WAS FELT TO BE AN IMPORTANT INITIATIVE AND ENDORSED UNANIMOUSLY. >> ANY QUESTIONS? NOW WE'LL MOVE TO COMPETITIVE RENEWAL OF THE AMP AB TARGET DISCOVERY AND PRE-CLINICAL VALIDATION PROJECT. RICHARD MAYO WILL REPORT. >> THIS WAS A CONCEPT TO ENHANCE THE AMP AD TARGET DISCOVERY PROGRAM, HAS DIRECT RELEVANCE TO AD, THE INTENT IS TO SHORTEN THE INTERVAL BETWEEN DISCOVERY AND GENOMICS PROTEOMIC AND METABALOMIC FINDING, MAKE THE -- THEM AVAILABLE FOR POTENTIALLY IDENTIFYING THERAPEUTIC TARGETS. THEY HAVE A SUBSTANTIAL AMOUNT OF DATA ALREADY, HAVE POSTMORTEM TISSUE, AND NOW UNDERGOING WHOLE GENOME SEQUENCING. THEY HAVE THERE IS A LIMITED BAND WITHTO ANALYZE DATA AND THAT DOESN'T GIVE SUFFICIENT TIME FOR PRE-CLINICAL VALIDATION SO THE REASON TO SUPPORT WAS FOR ANNOTATION AND INTEGRATION WITH OTHER AVAILABLE DATA SETS. AND NOVEMBERING INTO CELL SPECIFIC EXPRESSION, IMPLICATIONS. VALIDATION. SO WE ENTHUSIASTICICALLY SUPPORT. FROM. >> THANK YOU. ANY QUESTIONS? NEXT CONCEPT IS CHARACTERISTICS CAUSES, CONTEXT AND CONSEQUENCES OF THE ELDER MISTREATMENT. TERRY MOFFET WILL REPORT. COUNCIL UNANIMOUSLY APPROVEING A CONCEPT CLEARANCE WITH NEW RESEARCH INTO ELDER ABUSE. THE PREMISE BEHIND IS RESEARCH ON ELDER ABUSE IS PUSHED FORWARD MORE RAPIDLY, IF THE RFA REQUIRES TEAMS OF RESEARCHERS TO BRING THE FEELS OF CHILD MAL TREATMENT AND INTIMATE PARTNER VIOLENCE WITH EXPERTISE IN AGING AND ELDER ABUSE. THE TEAMS WILL IDENTIFY PREVENTION TARGETS AND CREATE NEW TOOLS TO MEASURE RISK. THEY'RE GOING TO STUDY BOTH VICTIMS OF ELDER ABUSE AND PERPETRATORS OF ELDER ABUSE. THIS CONCEPT CLEARANCE IS SUPPORTED BECAUSE IT ADDRESSES THREE SECTIONS OF NIH STRATEGIC PLAN. INCLUDING MAINTAINING THE DIGNITY, SAFETY, AND RIGHTS OF PEOPLE WITH ALZHEIMER'S DISEASE. >> THANK YOU. COMMENTS, QUESTIONS? THE NEXT CONCEPT IS SOCIO ECONOMIC DISPARITIES IN HEALTH AT OLDER AGES. AND RAYNARD KINGTON WILL REPORT. >> THIS IS PROPOSED REALLY BASED ON GROWING AMOUNT OF EVIDENCE WHEN YOU SOCIO ECONOMIC STATUS TO HEALTH ACROSS THE LIFE SPAN, NOTED THE JAMA ARTICLE, DR. BERNARD NOTED ON STATUS OF MORTALITY, GOAL IS FOCUSED ON INCOME, EDUCATIONAL ATTAINMENT AND GEOGRAPHIC REGION AND BUILT ON 2016 WORKSHOP, PRIORITY FOR INVESTMENT, UNANIMOUSLY ENDORSED. >> THANK YOU. QUESTIONS, COMMENTS? ALL RIGHT. THE NEXT CONCEPT IS COORDINATING CENTER FOR THE CLAUDE D. PEPPER OLDER AMERICANS INDEPENDENCE CENTER. EDWIN NEWMAN WILL REPORT. >> THIS WAS A CONCEPT PROPOSAL TO PUT OUT A COMPETITION FOR FORDNATEING CENTER FOR THE PEPPER CENTERS WHICH CONDUCT RESEARCH FOR INDEPENDENCE IN OLDER ADULTS THERE'S BEEN COORDINATING CENTER FUNDED FOR THE PAST TEN YEARS, THE MECHANISM NEEDS TO BE CHANGED BUT THEIR INITIATIVE IS NEEDED NOW BECAUSE THE COORDINATING CENTER THAT'S CURRENTLY FUND WILLED END IN 2018. THE COORDINATING CENTER HAS CONDUCTED A VARIETY OF ACTIVITIES AND THE PROPOSAL IS TO EXAND THE THE ACTIVITIES TO CONTINUE CURRENT FUNCTION, CONDUCTING AN ANNUAL MEETING, SHARING RESEARCH RESOURCES, AND FOSTERING COMMUNICATION AND TRAINING AMONG THE PEPPER CENTERS. THE NEW ACTIVITIES WOULD INCLUDE DEVELOPING MORE TECHNIQUES TO ENHANCE DATA SHARING AND GREATER SUPPORT FOR TRAINEES AS WELL AS MORE SUPPORT FOR INTERACTIVE WEB INTERFACE TO FURTHER ENHANCE INTERACTION. THIS PROPOSAL WAS UNANIMOUSLY APPROVED BY COUNCIL. >> THANK YOU. ANY QUESTIONS? LAST CONCEPT THAT WE WILL HAVE PRESENTED IS HIV AND AGING AND STEVE CUMMINGS WILL REPORT ON THAT. >> COUNCIL UNANIMOUSLY APPROVED THIS CONCEPT CLEARANCE, NIA HAS MONEY SET ASIDE FOR RESEARCH ON HIV AND AGING AND THAT'S BASED ON THE RATIONALE PATIENTS WITH HIV OR AGING AND BY 2020, HALF HIV INFECTED AMERICANS WILL BE OVER AGE 50. THAT'S EVIDENCE THAT HIV MAYBE A MODEL FOR ACCELERATED AGING BECAUSE OF INFECTION. ALSO BECAUSE OF ITS TREATMENTS. SO THEY HAVE AN INCREASE RISK OF CARDIOVASCULAR AND NEURODEGENERATIVE DISEASE. THERE'S ALSO UNDERLYING MOLECULAR EFFECTS OF HIV THAT RESEMBLE AGING, FOR EXAMPLE THE EFFECT CAUSING MITOCHONDRIAL DYSFUNCTION. THERE ARE A NUMBER OF SOCIAL PSYCHOLOGICAL IMPLICATIONS OF HIV INFECTION. AMONG THE OLDER POPULATION. SO COUNCIL APPROVED CONCEPT CLEARANCE FROM BROADER RESEARCH FROM BIOLOGICAL IMPACT, CELLULAR BIOLOGY OF HIV INFECTION RELATED TO AGING ALL THE WAY TO THE CONTRIBUTION OF SOCIAL AND PSYCHOLOGICAL FACTORS AFFECTING THE WELL BEING OF HIV PATIENTS. >> THANK YOU. TECHNICALLY IT'S THE WORKING GROUP RECOMMENDING TO COUNCIL, I WILL ASK FOR MOTION FOR APPROVAL FOR ALL THE CONCEPTS IN A MOMENT BUT I'M GOING TO ALSO REMIND YOU THAT WORKING GROUP RECOMMENDED TWO -- RECOMMENDING -- DEFERRING TWO ADDITIONAL CONCEPTS. SO WITH THOSE DEFERRALS ALSO FROM THE WORKING GROUP AND THE EIGHT CONCEPTS YOU DESCRIBED NOW ASKING FOR A MOTION TO APPROVE ALL THE WORKING GROUP RECOMMENDATIONS. THANK YOU. ANYBODY ONLY POSED? -- OPPOSED? ANY FURTHER DISCUSSION OR ABSTENTION? ALL RIGHT. ALL APPROVED. THANK YOU. >> THANK YOU. WE HAVE ONE ITEM THAT IS NOT ON THE AGENDA THAT WE'RE GOING TO SPEND A COUPLE OF MINUTES ON. THERE HAS BEEN AND ALL EXTERNAL PROGRAM REVIEW DONE BY THIS COUNCIL OVER THE LAST TWO YEARS AND THAT COMMITTEE WAS CHAIRED BY RICHARD MAYO AND RICHARD IS GOING TO REPORT BRIEFLY ON THE RECOMMENDATIONS. >> THANK YOU, EILEEN. OUR CHARGE WAS TO ASSESS THE ORGANIZATION OF INTERNAL AND EXTERNAL INTERACTIONS TO ADDRESS NEW OPPORTUNITIES AND CHALLENGE PROPOSED BY THE TRENDS IN BIOMEDICAL BEHAVIORAL RESEARCH AND ADVANCES IN AGING RESEARCH TO ASSESS PLANNING PROCESS IN NIA TO FACILITATE GOALS AND OBJECTIVES ACROSS THE DIVISION. WE FOUND CONSIDERABLE STRENGTH OUTSTANDING LEADERSHIP, INCREASING FUNDING FOR AD REMITTED RESEARCH AND DEVELOPMENT OF JOINT PROJECTS BEING PREPARED TACES REVIEW IS BEING -- PREPARED AS THE REVIEW IS BEING CONDUCTED. WE IDENTIFIED SOME WEAKNESSES, THERE WAS SMALL WORK FORCE BUT THAT WAS CORRECTED THIS MORNING WHEN WE SAW THE NUMBER OF PEOPLE HIRED, THAT'S A GOOD OUTCOME. WE ALSO RECOMMENDED PHENOTYPE HARMONIZATION BE CONSIDERED OF EXISTING IN FUTURE COHORTS. WE IDENTIFIED A POTENTIAL PROBLEM, GRANTS ARE CODED AND ASSOCIATED WITH ONE DIVISION AND AFFECTS THE INCENTIVE TO WORK WITH OTHER DIVISIONS, WE RECOMMENDED CHANGING THAT. EXTERNAL COMMUNICATION WE THOUGHT WAS LIMITED REGARDING PAY LINES AND FUNDING DECISIONS. HOPE THAT CAN BE CORRECTED. INTERNAL COMMUNICATION ACROSS THE DIVISIONS STILL REMAINS A PROBLEM AND IS LIMITED TO DIVISION DIRECTORS OR BRANCH CHIEFS. THERE WERE CONSIDERABLE OPPORTUNITIES TO ESTABLISH DOES CANNINGSES ON TRACKLATION ACROSS ALL DIVISIONS AND WITH THE INTRAMURAL PROGRAM, DEVELOP SYSTEM OF RECOGNITION AT THE INDIVIDUAL LEVEL FOR COLLABORATION ACROSS DIVISION, ESTABLISH CROSS DIVISIONAL PROGRAM OFFICERS TO FACILITATE COMMUNICATION, INTERACTION AND RESEARCH OPPORTUNITIES, STRONGLY ENCOURAGE -- INCREASE CROSS TALK AND PARTNERSHIPS WITH OTHER STAKEHOLDERS, AND AGING AND ALZHEIMER'S DISEASE PARTICULARLY CMS, PCORI AND THE BIOMEDICAL INDUSTRY AND FOUNDATION. WE ENCOURAGE NIA TO INFORM STAKEHOLDERS IN THE LAY COMMUNITY ABOUT THE EFFORTS ONGOING AT THE NIA AND THE IMPACT THE NIA IS MAKING ON THE HEALTH OF ELDERLY. WE RECOMMENDED AUGMENTING RESEARCH TRAINING IN AGING. FINALLY WE DID IDENTIFY A FEW THREATS THAT COULD BE EASILY -- COULD BE CORRECTED. THAT IS TO RECONSIDER FUNDING CONSTRAINTS ON THE SCIENCE INITIATIVE WHICH IS REALLY IMPORTANT INITIATIVE THAT WOULD CROSS DIVISIONS AT NIA, NIH PROGRAMS AND OTHER INSTITUTES. WE MADE A RECOMMENDATION THAT HUMAN RESOURCES SHOULD CONTINUE TO DEVELOP PORTFOLIOS RELEVANT TO AGING AND HEALTH, WE UNDERSTAND THIS IS AN NIH WIDE ISSUE BUT WE REALLY THINK IT'S IMPORTANT TO HAVE GOOD WELL TALENTED WELL TRAINED INDIVIDUALS TO WORK WITH NIH STAFF. TRANSPARENCY FOR OPPORTUNITIES AND OTHER DIVISIONS SHOULD BE CLEAR THE FINALLABLE RECOMMENDATION IS TO DEVELOP SOME METHOD WITH THE HELP OF THE CENTER FOR SCIENTIFIC REVIEW, TRANSDISCIPLINARY SCIENCES, NEVER WELL RECEIVED ESPECIALLY WHEN IT GOES TO SPECIAL EMPHASIS PANELS WHICH CAN CHANGE EVERY THREE TO SIX MONTHS. SO WE HOPE THAT SOMETHING COULD BE DONE TO FACILITATE TRANSDISCIPLINARY SCIENCE. >> THANK YOU, RICHARD, YOU MADE US A REAL WORKING GROUP THIS YEAR. THANK YOU VERY MUCH FOR YOUR LEADERSHIP. THAT'S THE END OF OUR -- >> JUST BEFORE THE BREAK I'M GOING TO MENTION THERE ARE STATISTICAL PACKAGES ON THE TABLE, THESE ARE JOINTLY DISTRIBUTION OF APPLICATIONS NUMBER OF APPLICATIONS FOR THE CURRENT COUNCIL ROUND, THERE'S ONE ALSO SHOWING FOR THE FULL YEAR 2016 HOW APPLICATIONS ARE DISTRIBUTED. THE OTHER REPORT THAT'S THERE IS THE ANNUAL DATA REPORT WHICH SHOWS OUR MONEY, THAT SHOWS HOW THE MONEY HAS COME IN OVER THE LAST FEW YEARS, HOW OUR SUCCESS RATE AND SOME OTHER DETAILS ABOUT THE DIFFERENT KINDS OF ACTIVITY THAT WE SUPPORT. WITH THAT, WE WILL RECONVENE AT 9:25 SO WE CAN INTRODUCE A FEW MORE STAFF. THANK YOU. >> SO AS PEOPLE ARE BEING SEATED SO THAT WE CAN STICK SOMEWHAT TO OUR TIME SCHEDULE, THERE ARE OTHER VERY IMPORTANT PEOPLE THAT WE FAILED TO ACKNOWLEDGE EARLIER. WE HAVE ADDITIONAL STAFF TO BE INTRODUCED AND WE HAVE VISITORS HERE SO I WILL ASK OFFICE DIRECTORS FROM NIA WHO ARE IN THE ROOM TO COME FORWARD TO INTRODUCE YOUR NEW STAFF MEMBERS AND ANY GUESTS HERE WHO WOULD LIKE TO INTRODUCE THEMSELVES PLEASE STAND UP AND DO SO. >> YOU WANT TO COME TO MICROPHONE SO WE CAN HEAR YOU? >> I'M MELINDA KELLY, HEAD OF LEDGE LACETIVE POLICY OFFICE AT NIA. I HAVE A NEW STAFF MEMBER DR. COURTNEY WALLACE BACK THERE, PRESIDENTIAL MANAGEMENT FELLOW AND JOINED MY OFFICE A COUPLE OF MONTHS AGO AND HAVE BEEN INSTRUMENTAL IN ACTIVITY SINCE THEN. SHE HAS A PERFECT BACKGROUND FOR OUR OFFICE IN TERMS OF PSYCHOLOGY AND COGNITIVE NEUROSCIENCE, VERY HAPPY TO HAVE HER AND SHE WILL BE WITH US AT LEAST UNTIL THE FALL AND MAYBE DOING ROTATIONS AROUND THE NIA. >> I WOULD LIKE TO INTRODUCE (INAUDIBLE). SHE'S Ph.D. FROM THE UNIVERSITY OF GEORGETOWN UNIVERSITY. SHE JOINS US AS SCIENTIFIC PROGRAM ANALYST FROM NHLBI AIDS PROGRAM. THEN MIA LOUDEN -- ALSO Ph.D. UNIVERSITY NORTH CAROLINA CHAPEL HILL, SHE DID POST-DOC UNIVERSITY OF VIRGINIA AND SHE WAS AT NIAID IN THE PLANNING OFFICE PRIOR TO JOINING US. THANK YOU. >> DR. LOUDEN HAS ARRIVED. >> I WOULD LIKE TO INTRODUCE NEW SCIENTIFIC PROGRAM OFFICER (INAUDIBLE) FROM MAYO SHE'S A -- (INDISCERNIBLE). >> ANY GUESTS WHO WOULD LIKE TO ACKNOWLEDGE THEMSELVES? ANYONE ELSE WHO NEEDS TO BE ACT KNOW ALMOSTED? MELISSA MCGOWN THERE, A NEW STAFF MEMBER IN THE OFFICE OF COMMUNICATIONS AND PUBLIC LIAISON, ONE BRANCH CHIEF THERE. >> WE WILL MOVE ON WITH THE AGENDA. DR. JOSE VELASQUZ WILL INTRODUCE DR. ROMASHKAN. >> WE'RE PLEASED TO HAVE WITH US TODAY, SHE'S AN ASSOCIATE PROFESSOR AND ASSOCIATE -- FROM STANFORD MEDICAL SAY SOCIOIATION IN CALIFORNIA. SHE OBTAINED HER MASTERS OF SCIENCE IN BIOCHEMISTRY 19 T 8, (INDISCERNIBLE) THEN SHE DID POST-DOCTORAL WORK IN KENYA AND IN CALIFORNIA, SHE BEGAN HER WORK AT SANFORD IN 2007. AND SHE HAS BEEN WORKING ON AUTOPHAGY SINCE THAT TIME IS A VERY EXCITING TOPIC. TODAY SHE WILL TALK ABOUT RECYCLING, THE ROLE OF AUTOPHAGY IN AGING AND DISEASE. >> THANK YOU VERY MUCH FOR THE INVITATION TO COME HERE FROM CALIFORNIA TO TELL YOU A LITTLE BIT ABOUT THE WORK THAT GOES ON IN OUR LAB. SO WE WILL GO REALLY BASIC HERE. IN OUR LAB WE USE C ELEGANS AND ALSO MAMMALIAN CELL CULTURE, TO STUDY THIS PRESENCE OF AUTOPHAGY AS A CANDIDATE MOLECULAR MECHANISM OF AGING. I'M GRATEFUL TO JOSE FOR INVITING ME, I WILL HIGHLIGHT THE RESEARCH THAT'S BEEN FACILITATED BY THE FUNDING FROM THE NIA. BUT BEFORE I WANT TO GIVE YOU AN OVERVIEW OF WHAT WE DO AND SHARE WITH YOU UNPUBLISHED STUDY, I WANT TO START BY ACKNOWLEDGING LAST YEAR'S NOBEL PRIZE WINNER, DR. S UKMI (PHONETIC), REALLY INSTRUMENTAL IN DOING THE VERY BASIC AND START WORK IN YEAST TO FIND MANY OF THESE GENES THAT NOW DEFINE THIS PROCESS OF AUTOPHAGY, CELLULAR RECYCLING PROCESS. WE WILL TELL YOU ABOUT WHAT THAT IS, THE CELL HAS THE CAPACITY TO DEVELOP MILLIONS OF YEARS AGO TO REQUEST COMPONENTS OF CYTOPLASM, MAYBE ORGANELLES LIKE MITOCHONDRIA OR RIBOSOMES, INTO THESE DOUBLE MEMBRANE STRUCTURES THAT CLOSE TO BECOME AN AUTOPHAGOSOME, IN A COMPLEX PROCESS WITH THIS LITTLE BAG ENZYME CALLED DEVICE THAT'S ACIDIC TO MEDIATE DEGRADATION OF COMPONENTS IN SIZE THAT CAN BE RECYCLED, INDUCED BY A NUMBER OF STRESSES, FOR INSTANCE REDUCE FOOD INTAKE. AND AGAIN THAT WOULD MEDIATE THIS RECYCLING OF MATERIALS BACK TO THE CELLS. (INAUDIBLE) IMAGINE A VERY COMPLEX PROCESS MORE THAN 40 PROTEINS IDENTIFIED, MANY OF THOSE WERE IDENTIFIED BY (INDISCERNIBLE) BUT ALSO CONSERVED IN WORMS AS YOU WILL SEE ONE OF THEM, I WILL TALK ABOUT BGG 8 ALSO KNOWN AS LC 3, IT'S A COMMON MARKER TO HIGHLIGHT THESE VESICLES. IN THE CELL. AND IN THAT WAY YOU CAN MONITOR AND QUANTIFY THE PROCESS. SO WE'RE INTERESTED IN AUTOPHAGY FOR A NUMBER OF OTHER REASONS INCLUDING THAT'S LINKED TO A NUMBER OF AGE RELATED DISEASES AND OFTEN COMPLEX WAYS YOU CAN SEE, THEN IT'S DIRECTLY LINKED TO AGING. I WOULD LIKE TO TELL YOU A LITTLE BIT ABOUT WHAT THE MAIN OBSERVATIONS HAVE BEEN TO THAT END. REALLY THERE'S BEEN A NUMBER OF CONSERVED PATHWAYS, THIS IS HERE REDUCED INSULIN SIGNALING YOU CAN (INAUDIBLE) FOOD INTAKE OR MTOR SIGNALING, MITOCHONDRIAL RES ARE ALL PARADIGMS, THAT SEEM TO BE COB SERVED IN A NUMBER OF -- CONSERVED IN A NUMBER OF MODEL ORGANISMS. THAT SEEMS TO HAPPEN AT LEAST IN C ELEGANS. BY SORT OF BOOSTING THIS PROCESS OF AUTOPHAGY ALSO CALLED MICROAUTOPHAGY. THIS IS THE FUNDAMENT FOR OUR LAB AND OUR STUDIES IN A NUMBER OF MODELINGS BUT I WILL SHOW YOU THE LINES OF EVIDENCE IN THIS GERM LINE REMOVAL MODEL SO THIS WAY OF REMOVING THE GERM LINE LIFE SPAN NOT ONLY IN WORMS BUT ALSO IN A NUMBER OF OTHER ORGANISMS. SO WE DO THIS IN C ELEGANS FOR A NUMBER OF REASONS, THEY HAVE A SHORT LIFE SPAN ONLY A COUPLE OF WEEKS, AND BY FAR THEY'RE GENETICALLY TRACTABLE, WE CAN ACTIVATE GENES EASILY BY FEEDING THE WORMS BACTERIA THAT EXPRESS DOUBLE STRANDED RNA TO DO EFFECTIVE RNAI WHERE INTERESTED. IN DOING SO. THE MAIN OBSERVATION THAT THIS WORK WAS INITIATED BY (INDISCERNIBLE) NOW ASSISTANT PROFESSOR AT BROWN UNIVERSITY WITH A FORMER GRAD STUDENT, SARA (INAUDIBLE) WAS TO CHARACTERIZE THE AUTOPHAGY PROCESS BY MEANS OF METHODS RECOGNIZED IN THE FIELD AND THE GOLD STANDARD BY ALL MEANS IS BY ELECTRON MICROSCOPY SO WE LOOK FOR THESE VESICLES AS A SIGN OF DEGRADATION OR DOUBLE STRUCTURE IN ANIMALS AND ADS YOU CAN SEE HERE, WE FOUND AN INCREASE NUMBER OF THOSE EVENTS IN THE INTESTINE OF THESE ANIMALS. WE USE AS MARKER I ALREADY MENTIONED TO YOU, TO BASICALLY LOOK AT AND QUANTIFY THESE DOTS THAT ARE REPRESENTING THESE ARTIFACTS EVENTS AND WE ALSO SAW THOSE INCREASE SO I WANT TO MAKE A POINT OF CAUTION HERE, THESE ARE WHAT WE CONSIDER STEADY STATE METHOD BY MEANS OF LOOKING AT THEM. THIS DOESN'T TELL YOU WHY YOU HAVE AN INCREASE IN THE NUMBER OF THAT BECAUSE YOU'RE MAKING MORE OR BECAUSE YOU CANNOT FINISH THE PROCESS, OBVIOUSLY THAT ALSO CAUSES ACCUMULATION OF THE VESICLES TO JUST SIT THERE. WE DO BELIEVE, I WILL COME BACK LATER IN THE TALK, WE DO BELIEVE THAT THE INCREASE IN THESE NUMBERS REPRESENT BOOST OF AUTOPHAGY OR INDUCTIONS OF AUTOPHAGY, BECAUSE WE DO A LOT OF TRANSCRIPTIONAL WORK LED BY -- TO SHOW THAT A NUMBER OF GENES WORKING IN MANY DIFFERENT STEPS, ARE SIGNIFICANT INCREASE IN LUNGS OF ANIMALS AS YOU CAN SEE, MOREOVER THESE GENES ARE REGULATED BY A WELL KNOWN TRANSCRIPTION FACTOR, YOU MAY HAVE HEARD OF IT CALLED HLA (INAUDIBLE) IN WORMS, THAT TRANSCRIPTION FACTOR LOCALIZED HERE, THE INTACT VERSION OF THAT TRANSCRIPTION FACTOR GOES TO NUCLEUS IN ALL THESE AND I SHOULD ADD PIERRE OBTAINED HIS FIRST RO1 FROM THE NIA TO STUDY THIS IMPORTANT TRANSCRIPTION FACTOR IN MORE DETAIL. PERHAPS MOST IMPORTANTLY WHAT WE SHOW AND NUMBER OF PEOPLE HAVE SHOWN IN OTHER MODELS IS EXPERIMENT WE BASICALLY GO AND BLOCK AUTOPHAGY, I SHOW A COUPLE OF GENES HERE BUT WE HAVE BEEN METHODICAL ABOUT KNOCKING DOWN GENES DIFFERENT STEPS OF THE PATHWAY TO ARGUE THAT IT'S JOINT PROCESS OF AUTOPHAGY THAT'S CRITICAL HERE TO SHOW THAT REDUCTION OF GENES AS YOU CAN SEE COLLAPSE THE LIFE SPAN BENEFITS OF THIS ANIMAL SO IN OTHER WORDS, IF THEY DON'T HAVE A FULLY CAPABLE AUTOPHAGY MACHINERY THE ANIMALS ARE NOT ABLE TO LIVE LONG SO WE TAKE THAT WITH A PREVIOUS EXPERIMENT TO SAY THAT AUTOPHAGY OR INCREASE AUTOPHAGY IS REQUIRED AT LEAST IN PART FOR THESE GERM LINE ANIMALS TO THIS MODEL. REALLY, SIMILAR LINES OF EVIDENCE HAVE BEEN CARRIED OUT BY NUMBER OF LABS TO PUT TOGETHER THIS MODEL THAT THESE MUTANTS SEEM TO BOOST AUTOPHAGY IN A BENEFICIAL WAY, BY SPREADING THEM WE CAN LEARN SOMETHING ABOUT THE AUTOPHAGY PROCESS AND LINK TO AGING. I ALSO WANT TO MENTION THIS IS JUST NOT -- YOU CAN SEE IN MAJORITY OF WORK LINKING LONGEVITY MODELS TO DIFFERENT GENES IN THE PATHWAY -- ALSO LINKS TO ARGUE AUTOPHAGY IN GENES ARE REQUIRED FOR LIFE SPAN EXTENSION. THERE'S ALSO THE IMPORTANT QUESTION OF WHETHER AUTOPHAGY INDUCTION IS SUFFICIENT, THIS IS STILL A WE THAT'S NOT -- STILL A QUESTION NOT ANSWER BUD THERE'S A NUMBER OF OVEREXPRESSION STUDIES INCLUDING OURS WHEN YOU OVEREXPRESS TRANSCRIPTION FACTORS THAT IS SUFFICIENT TO INCREASE LIFE SPAN AND ALSO DIFFERENT ASPECTS OF STANDARDS IN A NUMBER OF EXPERIMENTS WANTED IN MICE AS WELL, THOUGH WE DON'T KNOW IF THOSE MECHANISMS ARE BY AUTOPHAGY INDUCTIONS BY ITSELF, I SHOULD NOTE IN THE FIELD THERE'S A GROWING CONCEPT OF NON-CONVENTIONAL ROLES FOR AUTOPHAGY GENES OUTSIDE OF THE AUTOPHAGY PATHWAY. SO THIS IS A REALLY IMPORTANT AREA OF RESEARCH. WE ARE MAKING GREAT EFFORT TO EXPRESS MORE GENES TO THIS END TO GET SUFFICIENCY QUESTION THOUGH AT THIS POINT IT IS NOT YET CLEAR. REALLY TO ASK HOW IS THIS PROCESS REGULATED WHAT IS BEING TURNED OVER IN A BENEFICIAL WAY, WE ALSO REFER TO THAT AS THE CARGO, MEANING MATERIAL RECRUITED, AND WHEN AND WHERE IS THIS RELEVANT. THERE'S A NUMBER OF IMPACTS NOTED ABOUT THAT, LIKE IMPORTANT THERAPY FOR MANY AUTOPHAGY RELATED DISEASES. WE'RE INTERESTED IN CARGO IN TERMS OF KNOWING ABOUT THE PROTECTIVE CELLULAR MECHANISM IT IS CELL IS CAPABLE OF AND ULTIMATELY WE WOULD WANT TO TRANSLATE THIS INTO -- OBVIOUSLY WE NEED TO HAVE KNOWLEDGE ABOUT THE SITE AND TIME OF ACTION FOR THESE THINGS IN TERMS OF HOW TO TARGET AUTOPHAGY FOR THOSE BENEFITS. SO IN THE INTEREST OF TIME I WANT TO SUMMARIZE BRIEFLY SOME OF THE EFFORTS WE HAVE PUT FORWARD. WE HAVE MADE A LOT OF PROGRESS IN TERMS OF IDENTIFYING AND UNDERSTANDING BOTH POST TRANSLATIONAL AND TRANSCRIPTSAL REGULATORS OF THIS PROCESS IN THE CONCEPT OF AGING, MOST RECENTLY IN A IN TRANSCRIPTION FACTORS AND HOW IT LEADS TO KINETIC HEAT SHOCK WE CAN GIVE TO ANIMALS WELL KNOWN THAT CAN EXTEND LIFE SPAN AND WE HAVE LEANED IT IN A CO-REGULATION CAPACITY WITH A CLASSICAL HEAT SHOCK REQUIREMENT AND THIS CO-REGULATION OF AUTOPHAGY, HAPPY TO DISCUSS THAT LATER. THIS WAS SPEARHEADED BY LEWIS PIERRE WHEN HE WAS IN THE LAB. TO STUDY THE STUDIES WE BROUGHT FORWARD CONCEPT OF TURNING OVER LIPIDS WHICH WE HAVE FOUND BY GERM LINE IN THE ANIMALS TO BE REALLY IMPORTANT FOR MEDIATING AUTOPHAGY AND INTERPLAYING WITH AUTOPHAGY. WE'RE INTERESTED IN OTHER SPECIFIC AVENUES FOR INSTANCE, MY TO HAVE GIVE HAS A LIVE OF THEIR OWN, AND ALSO NEEDS TO BE TURNED OVER SO WE'RE INTERESTED IN THAT, THERE'S A RECENT PAPER IN NATURE TO SUGGEST LINKS IN THAT REGARD AS WELL. LASTLY ON WHEN AND WHERE, WE STARTED TO GET INTO THAT IN MORE DETAIL, I WANT TO SHARE WITH YOU UNPUBLISHED STUDY JESSICA CHEN WHO HAS DONE TREMENDOUS WORK DEVELOPING TOOLS AND REAGENTS AND ASSAYS FOR FIRST TIME TO MORE COMPREHENSIVE ANALYSIS OF AUTOPHAGY IN C ELEGANS IN TERMS OF UNDERSTANDING THE SPATIAL TEMPORAL REGULATION OF AUTOPHAGY IN C ELEGANS AGING. BASICALLY CHALLENGING THIS MODEL, IN THIS CASE SHE USED A WELL KNOWN CHARGIZED BY CYNTHIA KINNION MORE THAN 20 YEARS AGO AND GERM LINE ANIMALS THAT ARE MENTIONED TO YOU BEFORE. SHE WAS CURIOUS WHAT HAPPENS DURING NORMAL AGING THE FLIP SIDE OF OF THE AGING STUDY SO HER FIRST QUESTION WAS DOES AUTOPHAGY INCREASE OR DECREASE WITH AGE IN NORMAL ANIMALS. THE SECOND PART WOULD BE DO THESE ANIMALS INCREASE AUTOPHAGY IN TISSUE SPECIFIC WAY TO ENSURE LIFE SPAN EXTENSION? GETTING BACK TO THIS IDEA THAT WE'RE CURIOUS ABOUT WHAT'S GOING ON IN THE DIFFERENT TRAITS OF THE ANIMAL. SHE DEVELOPED A NUMBER OF ASSAYS WON'T GO INTO DEUNTIL TODAY BUT ALLOWED US TO QUANTIFY AND MONITOR THIS PROCESS OVER TIME IN DIFFERENT TISSUES SO THIS IS A LOT OF DATA BUT WHAT I WANT TO PICK UP ON MEASURED BY THIS MARKER VESICLES IN DIFFERENT TISSUES THEY ALL KIND OF GO UP WITH AGE. SEW THE QUESTION OBVIOUSLY BECOMES WHAT IS INCREASE IN AUTOPHAGY NUMBER REALLY MEAN. I CAUTIONED EARLIER AND THIS IS A STEADY STATE PROCESS TO MONITOR THE PROCESS. SO JESSICA DEVELOPED WHAT'S WELL KNOWN IN THE AUTOPHAGY FIELD, THE FLUX SYSTEM, THE POINT TO GIVE INHIBITOR OF THE SYSTEM THAT BASICALLY ALLOWS YOU TO ASK WHAT IS STATUS OF THIS RUNNING PROCESS AT THE TIME WHERE YOU GIVE THE INHIBITOR, IN THIS CASE WE USED WELL KNOWN LYSOSOME, THE WAY SHE LIVER DELIVERS IS SHE INJECTS INTO ANIMALS, RECOVERS FOR TWO HOURS, ENOUGH TO BRING THE SYSTEM INTO STEADY STATE, SHE CO-INJECTS WITH A BIGGER MYUNCLE GREWU O BECOMEA MY GRAND IN PERSPECTIVE CHANGED FREER SO I LEARNED A LONG TIME AGO NEVER EXPECT THE POSSIBILITY OF SOMETHING BEING IMPOSSIBLE. I HAVE TO SAY THAT WISDOM WAS A KEY PART OF P ME SURVIVING 23 YEARS, 57 ROUNDS OF CHEMOTHERAPY RADIATION BECAUSE A LOT OF PEOPLE SAID I WOULD BE DEAD MANY TIMES OR IT'S IMPOSSIBLE YOU WILL GET A KIDNEY TRANSPLANT SO I'M GLAD HE NOT ONLY GAVE ME GENETIC RESILIENCE BUT EMOTIONAL RESILIENCE AS WELL WITH THAT PHILOSOPHY. I THINK BECAUSE I WAS SO CLOSE TO HIM, WHEN I GO TO SETTINGS I FEEL I DO STILL TALK ABOUT THE AGING RESEARCH BECAUSE IT'S THE LAST TIME I DID REAL WORK. AND IT'S GREAT TO HAVE FRIENDS FROM THE ALZHEIMER'S ASSOCIATION HERE MY GRANDFATHER'S WIFE HAD ALZHEIMER'S AND AT AGE 16 I WAS A CAREGIVER FOR HER. SO I WAS CLOSE TO MY FAMILY BUT ALSO THE CHALLENGES OF AGING BECAME PART OF MY LIFE AT A VERY YOUNG IMPRESSIONABLE AGE. AND IT LED TO -- WHEN I USED TO DO RAW RESEARCH AS A SOCIAL SCIENTIST, I SPENT A LOT OF MY TIME DOING ETHNOGRAPHIC FIELD WORK OF THE ENTIRE CARE EXPERIENCE OF SENIORS AROUND THE COUNTRY SO THESE WERE ORIGINAL FIELD WORK. CARL IS ONE OF THE FIRST PEOPLE I STUDIED AND I WAS WITH HIM ON HIS JOURNEY TO FIGURE OUT WHAT WAS INITIALLY SHELTER PAIN -- SHOULDER PAIN WAS ONSET OF PARKINSONS AND IT TOOK A LONG TIME TO FIGURE OUT IN PART BECAUSE OF LACK OF DATA AND PART LACK OF KNOWLEDGE OF WHAT PHYSICIANS WERE ACTUALLY GIVING HIM FOR OTHER CHRONIC CONDITIONS THAT HE HAD. IN PART BECAUSE IT WASN'T PRESENTING IN THE QUOTE UNQUOTE CANONICAL WAY PARKINSON'S DID. THIS LED TO PARTICULAR WORK 16 YEARS AGO ABOUT DEVELOPING WEARABLES BECAUSE WE ANNUAL SMART PHONES AND WEARABLES WOULD COME, BASICALLY FIGURE OUT NOT JUST MONITOR FOR CLINICAL REASONS MOVEMENT AND ACTIVITIES OF DAILY LIVING AS PERHAPS NEW VITAL SIGNS BUT ALSO TO USE THE DATA TO DEVELOP TOOLS TO DEVELOP FAMILY CAREGIVERS AND ELDERLY PEOPLE THEMSELVES TO CONTINUE TO MAINTAIN THE CHOICE AND QUALITY OF LIFE THAT THEY WANTED. SO WE HAD THE PRINCIPLE VERY EARLY ON NOBODY CALLED IT BIG DATA, WE WANTED TO COLLECT A LARGE COHORT AND BUILD A 300 HOUSEHOLD COHORT WITH ELDERS WITH DR. (INDISCERNIBLE) WE GOT STARTD ON THAT WORK TOGETHER AND REALIZE THE SMALL SCALE 300 YOU STARTED TO HAVE INTERESTING SIGNAL IN THE NOISE OF THE SENSORS, BUT THE PHILOSOPHY WAS TO GIVE THE DATA THEMSELVES NOT JUST THE DATA BUT THE TOOLS, WITH COGNITIVE DECLINE AS WELL ABOUT YOU MAY NOT BE AWARE THAT YOU'RE MOST PHYSICALLY CAPABLE TIMES OF THE DAY ARE HERE, THIS IS THE BEST TIME TO WALK OR AT LEAST IN THE CASE OF PEOPLE WITH EARLY COGNITIVE DECLINE, HELPING IF YOU'RE STILL PAYING YOUR OWN BILLS YOU'RE MOST WITH IT THESE HOURS OF THE DAY SO THAT'S A GOOD TIME TO DO THIS. THOSE ARE JUST SOME EXAMPLES OF THE PHILOSOPHY OF COLLECT THE DATA TO LARGE SCALE TO SEE IF THERE'S -- UNDERSTANDING THE UNFOLDING OR INTERVENTION OR PREVENTION OF THE CONDITION AND USE DATA AND POWER TILES AND PROFESSIONAL AND FAMILY AND CARRY THAT FORWARD. YOU GET THE SHOCK OF WIDE RANGE OF THINGS FAMILY DO TO HELP PEOPLE COPE WITH EARLY STAGE DEMENTIA AND THAT PHILOSOPHY HOW DO YOU COLLECT MULTIPLE DATA TYPES NOT JUST CLINICAL DATA BUT CLINICAL DATA AND BEHAVIORAL DATA AND ENVIRONMENTAL DATA AND WHAT CAN YOU LEARN ABOUT THE COMPLEXITIES OF ILLNESS OR AN INDIVIDUAL AS WELL AS POPULATION BY HAVING MULTIPLE DATA STREAMS. IF YOU HAD TOLD ME BACK THEN THAT I WOULD EVER MOVE FROM SILICON VALLEY WHERE I WORKED 26 YEARS TO RUN THIS CRAZY WHITE HOUSE SPONSORED INITIATIVE THAT THE PRESIDENT LAUNCHED LAST YEAR IN THE STATE OF THE UNION I DON'T KNOW ADDRESS, I WOULD HAVE LOST THAT TIME CAPSULE BET BY A LONG SHOT. SO MUCH CAREER IS LEADING TO THIS MOMENT. I BOTH PERSONALLY AND PATIENT ADVOCACY WORK THAT I DO, TEACHING PEOPLE HOW TO GET PRECISE CARE BASED ON PERSONAL GOALS AS A PATIENT AND AS MUCH DATA AS YOU CAN ABOUT THEM INDIVIDUALLY, AS WELL AS EMPOWERING THEM TO HAVE ACCESS TO THEIR OWN DATA AND TOOLS THAT USE THOSE. THESE ARE FUNDAMENTAL CORE PRINCIPLES OF WHAT WE'RE TRYING TO DO IN THE PMI PROGRAM. PMI PRECISION MEDICINE INITIATIVE STANDS FOR A BROAD SET OF INVESTMENTS BY THE FEDERAL GOVERNMENT, ONE OF THE LARGEST IS OUR PROGRAM WHICH WAS INITIALLY CALLED THE COHORT PROGRAM, THAT DIDN'T MEAN VERY MUCH FOR PARTICIPANTS, SOME ARE VERY PARTICIPANT CENTERED GROUP BUILDING THINGS OUT THAT MATTER AND WE BELIEVE PERSISTS, PARTLY INSTITUTED INTO THE CARES BILL RECENTLY PASSED. AND THOSE HAVE BEEN PART ACROSS MULTIPLE PARTS OF NIH, AWARDS NCI YOU HEARD THE CANCER MOON SHOT, THERE ARE -- THESE ARE ALL PART OF THE PMI PORTFOLIO. THERE'S MULTIPLE AGENCIES WORKING THEM TOGETHER. SO WE SIT WITHIN THE ANCHOR TENANTS OF THE LARGEST PRECISION MEDICINE INITIATIVE. SO OUR NEW NAME IS THE ALL OF US RESEARCH PROGRAM, WE HAD FEEDBACK FROM PARTICIPANTS EARLY ON A LOT OF BIG GOALS IS TO RECRUIT UNDER-REPRESENTED BIOMEDICAL RESEARCH, I WILL WALK THROUGH AUDACIOUS ASPIRATION IN THAT REGARD IN A MOMENT. COHORT DID NOT RESONATE WITH FOLKS NOT IN A COHORT BEFORE, THE MAJORITY OF THE UNITED STATES. AND THIS NAME REALLY CAPTURES THE ESSENCE OF WHAT WE'RE TRYING TO DO AND THE SPIRIT OF THIS PROGRAM. SO THAT WAS OUR NAME CHANGE RECENTLY. SO LET ME ASSUME THAT SOME OF YOU KNOW A LOT BUT SOME MAY NOT KNOW ANYTHING ABOUT THE PROGRAM AND GIVE YOU QUICK OVERVIEW OF THE PROGRAM. OUR MISSION IS REALLY FUNDAMENTALLY TO ACT SEMIRATE SCIENTIFIC DISCOVERY AND BREAK THROUGHS IN PRECISION MEDICINE. WE ARE BUILDING A,NANAL RESOURCE THAT WILL OVER TIME BUILD A RICHNESS OF NOT JUST CLINICAL EHR DATA ENVIRONMENTAL LIFESTYLE, GENETIC DATA, AT LEAST 1 MILLION PARTICIPANTS FROM ACROSS THE COUNTRY, THESE ARE CONSENTED FOR A LONGITUDINAL HOPEFULLY LIFE LONG PERSPECTIVE STUDY, WE DON'T HAVE THE MONEY TO DO IT BUT NEITHER DID FRAMINGHAM WHEN IT STARTED. WE'RE DEVELOPING A TEN YEAR PLAN AND THERE'S MONEY ON TOP OF OUR BASE BUDGET AND CURES FOR THE NEXT TEN YEARS. RIGHT NOW WE'RE STARTING TO WORK ON A TEN YEAR PLAN IN THAT REGARD BUT WE HAVE AN EYE TOWARDS A LIFE LONG STUDY. THE PRIORITY IS TO REFLECT THE BROAD DIVERSITY OF THE UNITED STATES WITH A DIVERSE DEFINITION OF DIVERSITY. ALL AGES RACES ETHNICITY, GENDER, SOCIO ECONOMIC STATUS GEOGRAPHY AND RANGE OF GEOGRAPHICAL CONDITIONS AND WE'RE GOING TO OVERRECRUIT SIGNIFICANTLY THOSE UNDER-REPRESENTED BIOMEDICAL RESEARCH RESEARCH. THE OTHER PRIORITY IS NOT ONLY TO BROADEN SO THAT ALL OF US CAN BE PART OF A LARGE BIOMEDICAL STUDY, BUT TO FACILITATE AS MUCH AS POSSIBLE ALL OF US BEING ABLE TO HAVE ACCESS TO THE DATA TO DO RESEARCH INCLUDING CITIZEN SCIENCES. THERE'S NO DOUBT THAT EVEN TR 1 TOP FUNDED AWARDEES AND MEDICAL CENTERS FROM NIH WILL FIND THIS RESOURCE USEFUL AND CAN'T WAIT TO USE IT BUT WE WILL MAKE INVESTMENTS TO HELP OTHER PARTS RESEARCH CONTINUUM PARTS BAIT IN BIOMEDICAL RESEARCH, THEY HAD TO BUILD THEIR OWN COHORT OR LEARN ENORMOUS AMOUNT HOW TO SEQUENCE AND MAKE THAT DATA WIDELY AVAILABLE TO EVERYBODY WITH TIERS OF ACCESS BASED ON RISK OF REIDENTIFICATION OF THOSE PARTICIPANTS. SO WE OFTEN TALK QUADRUPLE DIVERSITY, THE DIVERSITY OF PEOPLE, HEALTH STATUS, SO A RANGE OF HEALTH CONDITIONS, GEOGRAPHY AND THEN RANGE OF DATA TYPES ESPECIALLY INCLUDING M HEALTH COMING FROM PHONES AND OTHERS, BUT WE DON'T KNOW HOW TO SEPARATE THE WEAK FROM THE -- SCIENTIFICICALLY AND HOW MUCH IS USEFUL AND HOW MUCH IS USEFUL ONLY FOR DIRECTIONAL PURPOSES BUT DOESN'T HAVE ANY DEEP CLINICAL VALUE FOR THE PARTICIPANTS. WE HAVE BUILT HEALTH PROVIDERS ORGANIZATIONS, EXPANDING OVER TIME AND RECRUISING AND DOING BIOSAMMING P COLLECTION AND PHYSICAL EVALUATION AND LONGITUDINAL RELATIONSHIP AS A HEALTHCARE ENTITY AND WHAT WE CALL DV, THE DIRECT VOLUNTEER PATH. WE'RE BUILDING OUT THE CAPACITY, WE WON'T HAVE IT ALL NATIONWIDE OUT OF THE GATE BUT FILLS QUICKLY OVER TIME. TO DO THE RELIABLE BLOOD DRAWS AND URINE COLLECTIONS AND FISCAL EVALUATIONS, FOR ANYBODY IN THE COUNTRY WHO SAYS THEY WANT TO BE PART. 1800 NUMBER, WEBSITES TO JOIN, BROCHURES, POSTERS SENT TO EVERY CLINICAL OFFICE WE CAN IN THE UNITED STATES. THIS PRESENTS CHALLENGES SOME WHICH WE'LL TALK ABOUT IN A MOMENT. I FREAKED OUT OUR PIs, WE HAVE A TWO DAY EVENT YESTERDAY AND TODAY AND I SAID THESE NUMBERS THAT WE MADE UP THAT SAYS 350,000 ARE GOING TO COME WE HAVE ABSOLUTELY NO IDEA. NOBODY AT SCALE HAS EVER DONE THIS. AND NOBODY AT SCALE HAS MANAGED TO DO IT TO RECRUIT AND SUSTAIN A LIFE LONG RELATIONSHIP WITH DIVERSITY OF COMMUNITY TO PUT INTO THIS AND MANY COMMUNITIES ARE >> HAD FEDERALLY FUNDED RESEARCH SO HOW DO YOU BUILD THE COVENANT WITH A DIFFERENT PROFILE THAN TRADITIONALLY SEEN IN CLINICAL TRIALS AND BIOMEDICAL RESEARCH. SO THESE ARE SOME OF THE CORE VALUES PARTICIPATION IS OPEN TO ALL INTERESTED. IT WILL REFLECT THE DIVERSITY OF UNITED STATES, PARTICIPANTS WILL BE PARTNERS IN THE PROGRAM, HELPING TO FIGURE WHAT RESEARCH ARE WE GOING TO DO, WHAT CAPABILITY TO ALLOW THE DATA, HOW WE DEAL WITH RETURN OF RESULTS AND GENETIC INFORMATION ONCE WE DO SEQUENCING OR GENOTYPING AND SEQUENCING. TRUST WILL BE EARNED THROUGH ENGAGEMENT AND FULL TRANSPARENCY. I ALREADY AM BUT SOON MORE SO TALKING TO PEOPLE ABOUT LAUNCHING THESE DATES BUT THE SECURITY TESTING DIDN'T GO WELL AND WE'RE NOT CONFIDENT WE'RE LAUNCHING YET SO I'M SORRY WE SAID WE WOULD LAUNCH AT THIS POINT BUT WE'RE GOING THE WAIT. A LEGAL OF TRANSPARENCY THE PEOPLE DESERVE AND RESEARCH COMMUNITY DESERVE AND VERY OPEN AND HONEST THIS IS FRIGHTENING FOR PEOPLE WHO HAVE NEVER DONE THIS BEFORE TO SCALE AND WE WILL LEARN AND MAKE MISTAKES AND WE'RE GOING TO IMPROVE AS WE GO FORWARD IN TIME. TONS OF ETHICAL ISSUES TO WORK THROUGH DEPENDING ON THE DATA TYPES. TONS OF PRACTICAL ISSUES TO GIVE PEOPLE BACK THEIR RAW DATA AT SCALE AS WELL AS INFORMATION SPECIFICALLY AND STUDIES COMING OUT OF ANCILLARY STUDIES. THERE WILL BE HOPEFULLY HUNDREDS IF NOT THOUSANDS OF ANCILLARY STUDIES ON TOP OF THIS RESOURCE, WE DON'T HAVE THE FUNDING TO DO MORE THAN PILOTING AND THE RELATIONSHIPS WITH THE REST OF THE INSTITUTES AND CENTERS AND OUTSIDE FUNDERS IS KEY AND I WILL TALK ABOUT THAT MORE IN A MOMENT. WE CERTAINLY PRIVACY AND TRUST AND SECURE NET DATA ARE ONE THING I LOOSE SLEEP ABOUT NIGHTLY. THIS IS NO DOUBT A TARGET USING MODERN TOP OF THE LINE INDUSTRY AND MILITARY AND OTHER PART OF THE GOVERNMENT TO BUILD INFRASTRUCTURE BUT WE HAVE TO ASSUME A BREECH WILL HAPPEN, AS PART OF THE COVENANT AND HONESTY ABOUT IF THIS HAPPENS THIS IS HOW WE COMMUNICATE WITH YOU AND BUILD EXPECTATIONS AROUND DOING THE BEST WE CAN BUT HERE IS WHAT WE WILL DO IN THE EVENT OF A BREACH. HERE IS POTENTIAL RISK TO YOU IF THAT BREACH SHOULD HAPPEN AND TRYING TO BE A CATALYST FOR INNOVATIVE RESEARCH PROGRAMS AND POLICIES. ONE EARLY PARTS OF NIH MOVED TO A CENTRAL IRB THOUGH VERY CLEAR TO THE FOLKS ON THE RFA THEY SOMEHOW DIDN'T NOTICE THAT PART AND CAME IN IN THEIR UNIVERSITY -- NO, WE HAVE TO GO THROUGH IRB, CENTRAL IRB THAT'S CHALLENGING BECAUSE OF STATE LAWS THAT ARE DIFFERENT IN THESE ISSUES BUT WE'RE WORKING THROUGH THAT SO I THINK DR. COLLINS SOMETIMES THROW THINGS IN HERE HE KNEW WAS GOING TO WANT TO MOVE THE REST OF THE NIH TO AND IC DIRECTORS SAID THEY WANT TO DO BUT HEY, LET'S LET ERIC'S TEAM FIGURE HOW TO DO THAT AND MAKE THE PAIN AND SUFFERING AND IT'S A GREAT THING. THE FOUR MAJOR BLOCKS ARE DRC DATA RESEARCH SUPPORT CENTER, THE DRC IS ALL ABOUT BUILDING THE DATA LAKE AND THE INFRASTRUCTURE AS WELL AS TOOLS RESEARCHERS USE ON TOP OF THE PLATFORM OR RESOURCE TO MAKE IT AVAILABLE TO WIDE RANGE OF AUDIENCES, THE BIOBANK IS THE BIOBANK AND INITIAL PROTOCOL BIOSAMPLES BLOOD AND URINE BUT CERTAINLY EXPECT MULTIPLE OTHER KINDS OF COLLECTIONS NOT JUST ADDITIONAL BLOOD AND URINE IN THE FUTURE BUT OTHER BIOSAMPLES AS WELL. THE PTC IS PARTICIPANT TECHNOLOGY CENTER SO EVERYBODY CONSUMER OR EVERYBODY PARTICIPANT FACING. THE 1800 NUMBER, APPS TO SIGN UP A P LOOK AT PROGRESS ONLINE. THE WEB PAGES, THE MOBILE BANDS TO HELP PEOPLE NOT DIGITALLY LITERATE TO SIGN UP AND BE PART OF THE STUDY, EVERYTHING IS PATER PANT FACING THERE AND NETWORK PROVIDER, THEY RANGE FROM REGIONAL MEDICAL CENTERS AND LARGE INTEGRATIVE NETWORKS FROM CARE TO PAY TO SMALL FRIENDLY QUALIFIED HEALTH CENTERS AND THE VA AS A STRATEGIC PARTNER AND WILL EXPAND THE NETWORK OF VA PARTICIPANT ADS WE GO OUT IN TIME. IT IS IMPORTANT TO UNDERSTAND WE ARE BUILDING THE FOUNDATION FOR OTHERS LIKE YOU TO STUDY AND WHAT WE'RE GOING TO LAUNCH PILOT PHASE SOON AND HOPEFULLY MIDSUMMER FUM NATIONAL LAUNCH IS VERSION 1 PLATFORM WHICH PARTICULAR SCIENTIFIC AREAS AND DATA TYPES AND SAMPLES AND ANALYSES AND TOOLS DO NOT -- A LOT OF INSTITUTES AND A LOT OF COUNCIL THAT I SPOKE TO ARE LIKE THIS IS OUR ONE CHANCE TO GET INPUT. I'M LIKE WE ARE EMBARKING ON A 50 TO # 0 YEAR JOURNEY TOGETHER AND THERE'S A NEW RELEASE OF A PLATFORM AND BY PLATFORM I THINK EVERYTHING FROM NEW KINDS OF PERSONNEL AND SERVICES FOR CONSUMERS OR PARTICIPANTS TO NEW RESEARCH TOOLS, EVERY TIME WE LAUNCH A NEW VERSION THAT COULD BE 18 TO 30 MONTHS, THERE'S GOING TO BE ADDITIONAL DATA, ADDITIONAL SAMPLES, ADDITIONAL ANALYSES TOOLS AND COHORTS. EVERYBODY IS CONSENTED AND WE'RE MANAGING EXPECTATIONS, THIS IS GOING TO BE MORE FRAMINGHAM LIKE IN TERMS OF FREQUENCY OF INTERACTION PROBABLY BUT MORE SO FOR SOME OVER A PERIOD OF TIME. V 3, WHATEVER, DOT, DOT, DOT, INTO THE FUTURE. WE WILL FUND PILOTS AIMING DOWN, LET'S SEE WHAT WE'RE CREATING, LET'S FUND AN ENVIRONMENTAL RISK STUDY AND WE WILL DO THAT WITHIN OUR PARTICULAR CONSORTIUM TO MAKE SURE THE INFRASTRUCTURE THAT WE'RE BUILDING OUT AND THE DATA THAT WE'RE COLLECTING FACILITATES THAT KIND OF STUDY. THESE HELP US KNOW WHAT NEW CAPABILITIES BACK IN. HEY SINCE WE'RE GOING TO STUDY PEOPLE LONGITUDINALLY, THERE'S INSTRUMENTS OR MEASURES OR SOMETHING THAT WE WANT TO DO, THOSE STATEMENTS, PROPOSING ARE GOING TO VALUE OTHER FIELDS AS WELL, YOU DECIDE TO PUT THOSE INTO THE CORE PROTOCOL OR NEXT PLATFORM FOR ALL MILLION PEOPLE, WE PILOT THOSE AND SEE AFFORDABLE AND WORK AND SMALLER NUMBERS BUT CAN YOU SCALE IT, AND SCALING PROBLEMS ARE HUGE. A LOT OF THE MORE DIVERSE STUDIES THAT HAVE DONE IN TERMS OF RECRUITMENT, THE AMOUNT OF MONEY SPENT FOR RECRUITMENT, OKAY AT SCALE, COST EFFICIENCY OR THAT MORE IN SMALL STUDY AND OTHER PILOTS ON THAT ARE INTERESTED IN AND LOOKING AT SECONDARY ANALYSIS OR ANCILLARY STUDIES WE'RE WORKING ON THE PROCESSES NOW LAYING OUT WHAT IS THE DATA BIOSAMPLE AND COHORT THEMSELVES ACCESS. THERE WILL BE A LOT BEFORE WE HAVE ENOUGH DATA TO BE MEANINGFUL, IT TAKES THREE AND A HALF TO FOUR YEARS TO GET THE A MILLION PEOPLE BUT WE DON'T KNOW, WE'RE GOING TO DISCOVER THAT'S CERTAINLY OUR GOAL, THAT'S CERTAINLY WHAT WE'RE BUILDING UP THE PLANS TO DO. SO QUICK UPDATE, THE CLOCK ISN'T MOVING, IT IS MOVING. I'M SPEAKING REALLY FAST, APOLOGIES. YOU CAN TELL I'M A LITTLE PASSIONATE AND I WANT YOU TO KNOW EVERYTHING YOU CAN KNOW BECAUSE PARTNERSHIPS WITH NIA IN PARTICULAR ARE SOMETHING THAT I'M EAGER TO EXPLORE BUT YOU HAVE TO LET US GET THE VERSION ONE OFF THE GROUND WE CAN'T LOAD EVERYTHING INTO VERSION 1, IT WILL COLLAPSE UNDER ITS OWN WEIGHT. SO WE BUILT THIS INITIAL NETWORK OF MORE THAN 50 WAR WAR DEES, THEY'RE COLLABORATING WELL. THEY'RE MAD AT ME ABOUT THINGS YESTERDAY BUT WE WALKED OUT FACE TO FACE FEELING LIKE WE SORTED THAT OUT. IT'S CLASSIC GROWING PAINS OF A GROUP THAT KICKED OFF IN JULY TRYING TO DELIVER UNPRECEDENTED PLATFORM IN A REPORT AMOUNT OF TIME AND COMING FROM A LOT OF DIFFERENT CULTURES, YOU WILL SEE WE HAVE DIFFERENT PLAYERS AND TRADITIONAL CLINICAL MEDICAL CENTERS THAT MOST OF YOU RECOGNIZE. THE PROTOCOL IS SUBMITTED FOR APPROVAL IN DECEMBER 23RD, TOMORROW IS A BIG DAY FOR A LOT OF US, THE ENTIRE COUNTRY COULD CHANGE BUT WE ALSO ARE GOING TO GET IRB FEEDBACK ON OUR END TO END PROTOCOL. WE HAVE COMPLETED A WHOLE RANGE OF COMMUNITY WORKSHOPS AND OUTREACH PLANS AND WE HAVE GOT A NOTICE OF INTENT TO PUBLISH OUT THAT TALKS FORTHCOMING AWARD FOR COMMUNITY PARTNERS AROUND SO TRUE COMMUNITY VOLUNTEERS ARE SET UP TO ACCOMMODATE ANYBODY, I WANT TO RAISE MY HAND TO BE PART BUT WE'RE NOT WAITING SO WE'RE FUNDING COMMUNITY AWARD, CHURCHES NOT FOR PROFITS LOOING DA, NATIONAL, REGIONAL Z TO RECRUIT AND BUILD RELATIONSHIPS PARTICULARLY GEOGRAPHIES WE DON'T HAVE GOOD COVERAGE YET AND COMMUNITIES THAT ARE HARD TO REACH AND THEY ARE KEY PART TO BE ABLE TO DO THAT. NEW NAME, WE'RE TESTING THE CONTENT AND BRAND, ENGLISH AND SPANISH AND WE HOPE TO ENCRIES THOSE LANGUAGES OVER PERIODS OF TIME. WE'RE ALMOST COMPLETE WITH THE WEBSITE, THE SMART PHONE APPS ALL DATA CENTERS, THE BIOBANK IS BUILDING MORE CAPACITY, THEY HAVE BUILDINGS THAT -- WE HAVE CAPACITY THERE, WE'RE TESTING WITH WATER FROM ALL OF THE LOCATIONS, 24 BY 7 NOT 24 BY 7, SHIP WITHIN 24 HOURS, WE BUILD THAT SHIPPING INFRASTRUCTURE FROM AROUND THE COUNTRY AND THE LABS AND CAPABILITIES THAT WE'RE BUILDING ARE OPEN NIGHTS AN WEEKENDS BECAUSE AS MANY OF YOU KNOW, ONE KEYS TO GET PEEP INTO RESEARCH STUDIES, IS YOU CAN'T DO IT FROM NINE TO 5, MONDAY THROUGH FRIDAY BECAUSE PEOPLE CAN'T GET OFF WORK TO COME THERE. WE'RE TESTING THE IT INTERFACES, THERE'S ENORMOUS SECURITY TESTING AND PROBABLY MID MARCH WE'LL HAVE A HACK ON THIS THAT OPENS UP EVERYTHING TOP AUDIENCES TO HACK THE HECK OUT OF IT. AND ULTIMATELY THE BIOBANK WE'RE PLANNING FOR 35 MILLION VILES, THAT'S A LOT TO TRACK AND DEAL WITH. AND THEN WE GET BETA FEEDBACK FROM PARTICIPANTS FROM BROAD COMMUNITIES AND EVERYTHING FROM THE NAME, THE LANGUAGE, THE USER INTERFACE, THE QUESTIONNAIRES, AND TRYING IS TO HONE ALL OF THAT, SO ENORMOUS ENTERPRISE, THIS IS THE INITIAL NETWORK WE'RE TRYING TO LAUNCH SO THE DARK BLUE ARE THE BIOBANKS, THE DRC, THE PTC AND WE DID PUT BLOCKS UNDER FEDERAL PARTNERS THAT'S BACK TO THE PRECISION MEDICINE INITIATIVE IS BROADER THAN OUR STUDY AND BROADER THAN NIH AND INCLUDES A LOT OF OTHER AGENCIES THAT ARE PULLING US TOGETHER. YOU CAN SEE EACH OF THOSE AWARDS OFTEN HAVE MANY PEOPLE UNDERNEATH IT. THERE WILL BE ADDITIONAL COMMUNITY PARTNER AWARDS THROUGHOUT THE YEAR AS WE EXPAND THE NETWORK. HERE IS ANOTHER DIAGRAM, EVERYTHING ON TOP IS ALL THE FOLKS WORKING ON THE DIRECT VOLUNTEER PATH THAT INCLUDES FOLKS LIKE WEB MD, WE'RE USING WALGREENS AND OTHER INFRASTRUCTURE NATIONAL BLOOD COLLABORATIVE, WHO ARE HELPING BUILD OUT THAT NETWORK TO BE ABLE TO DO RELIABLE BLOOD DRAWS AND BIOSAMPLE COLLECTIONS AND PHYSICAL EVALUATIONS WHERE THERE IS NOT AN ACADEMIC MEDICAL RESEARCH CENTER AND CREATE CHOICE FOR PARTICIPANTS. IN SOME CASES THEY MAY HAVE HEALTH PROVIDER ORGANIZATION THEY'RE PART OF OR GO DIRECT VOLUNTEER PATH. WE HOPE THEY GO HEALTH PROVIDER PATH BECAUSE IT HELPS THE EHR DATA. THEY HAVE THE CHOICE, IF THEY WANT TO DO IT CAPACITY NEAR THEM THEY CAN GO THE OTHER ROUTE. BELOW THE LINE ARE DIFFERENT HEALTH PROVIDER ORGANIZATION AWARDS. AND WE HAVE COMPANIES LIKE -- MOST OF YOU PROBABLY NEVER HEARD OF, LA COMMUNICATIONS AND DESIGN FIRM THAT HELPS US BUILD COLLATERAL AND COMMERCIAL AND RADIO ADS AND ALL THE OTHER THINGS THAT WILL GO OUT IN REGARDS TO THIS. SO QUITE A NETWORK. YOU CAN IMAGINE TAKING THESE DIFFERENT AWARDEES BUT BASICALLY, YOU HAVE TO ADMIT, THIS IS PROBABLY WHY I ENDED UP HERE, I WAS ON THE ACD WORKING GROUP FOR THIS, WHICH IS HOW I GOT SUCKED INTO IT. I KEPT SAYING THEY'RE BUILDING A PLATFORM AND THIS IS A DIFFERENT THING FOR NIH TO DO. IF YOU DON'T BRING PEOPLE IN, YOU WILL KNOW HOW TO BUILD SUSTAINABLE PLATFORMS THEN DON'T CONFUSE YOURSELF. SO WE ARE TRYING TO BRING IN FOLKS LIKE VERILEE FROM TECHNOLOGY INDUSTRY AND OTHERS TO MAKE SURE WE'RE BUILDING THIS IN A WAY IN'S REPLICABLE AND SUSTAINABLE AND THAT IS AFFORDABLE OVER TIME. IN TERMS OF ESTIMATE OF THE TARGET DEMOGRAPHIC AT LAUNCH, THESE ARE HEALTHCARE PROVIDERS ORGANIZATIONS AND DIRECT VOLUNTEER PARTNERS AND AWARDS HAVE TOLD US THEY THINK THEY CAN GET SO THIS IS A VIEW FROM RACIAL ETHNIC PERSPECTIVE IN TERMS OF PERCENTAGES WE'RE AIMING FOR AS WE GET TO A MILLION SO ABOUT 5050 IN TERMS OF MINORITY AND LIFE, THE BLUE ARE THE STATES WE HAVE HEALTH PROVIDER ORGANIZATIONS IN, IT DOESN'T MEAN WE HAVE FULL COVERAGE OF THE STATE, WE HAVE IT BY ZIP CODE BUT I COULDN'T GET THEM INTO THE POWERPOINT. AND WE'RE WORK COMPASSIONTY FOR THE DIRECT VOLUNTEER IN ALL STATES BUT IT WILL START A COUPLE OF STATES, PREED SO A REGION, MOVE TO ANOTHER REGION AND EVENTUALLY WILL HAVE MOST UNITED STATES COVERED. AS -- IF YOU LOOK AT OTHER ASPECTS OF THOSE UNDER-REPRESENTED BIOMEDICAL RESEARCH IN TERMS OF WOMEN, SEXUAL AND GENDER MINORITIES, LOW SES, PEOPLE IN RURAL AREAS, THE PHYSICALLY AND MENTALLY CHALLENGED, OUR GOAL OVER TIME, IS TO MAKE SURE AS WE BUILD THIS MILLION, 75% UNDER-REPRESENTED BIOMEDICAL RESEARCH. THIS IS A PRETTY AUDACIOUS GOAL MADE A LOT OF THESE FOLKS WHO SAID YEAH WE KNOW HOW TO GET SUSTAINED LONG TERM RELATIONS WITH THEM, THEY'RE TURNING BACK ON THEIR NUMBERS NOW, WE'RE NOT GOING TO THROW YOU OUT IF YOU DON'T MEET YOUR NUMBER, IT'S NOT ABOUT NUMBERS, IT'S BUILDING METHODS TO BUILD AND SUSTAIN RELATIONSHIPS, WE WILL LEARN HOW TO DO THAT, MORE OF THIS, LESS OF THE -- AND THE STUDY ITSELF IS HOW TO DO STUDIES IN THIS WAY, PUBLISHING RESULTS PROBABLY THE SOONEST PUBLISHED WILL BE PRACTICAL THINGS WHAT WE'RE LEARNING HOW TO TRY TO DO A COHORT AT THIS SCALE AND WITH THIS DIVERSITY. AS I MENTION BEFORE, THIS IS THE PROJECTED TIME LINE IN TERMS OF YEARLY PROJECTIONS. IF YOU WANT I'LL COME BACK EVERY YEAR AND HOW GOOD WAS OUR PREDICTIONS? HOPEFULLY BETTER THAN HURRICANE FOR KASTERS BUT WE COULD -- CORE FASTERS BUT WE -- O FORECASTERS. I'M GOING TO FLY THREW THIS BUT I WANT TO GET A CONSENT SO THERE'S eCONCEPT AND THERE'S HELPERS FOR THOSE WHO ARE NOT ELECTRONICALLY SAVVY, THE CONSENT ITSELF TRYING TO TURN INTO PLAYFUL NOT QUITE THE RIGHT WORD BUT PLEASANT, VIDEOS AND INTERACTIVITY TO TO MAKE SURE PEOPLE DO UNDERSTAND WHAT THEY'RE SIGNING UP FOR AND IT'S NOT JUST READING AN END USER LICENSE AGREEMENT FOR YOUR NEXT MICROSOFT OR APPLE SOFTWARE, YOU CLICK HERE AND GO ON SO EVEN THE CAPABILITIES THAT WE HAVE GOT CAN MAKE SURVEYS AND CONSENT VERY INTERACTIVE WITH RICH CONTENT TO EXPLAIN TO PEOPLE AND CONTEXT AWARE IN TERMS OF BASED ON ANSWERS YOU PUT SOMEWHERE WE CAN DO SMART THINGS AND NOT BUG YOU WITH OTHER THINGS NOT RELEVANT. SO WE'RE BUILDING A MODERN INFRASTRUCTURE FOR THIS. THESE ARE THE FIRST EIGHT PPI STANDSTOR PARENT PANT SURVEY MODELS WE'RE WORKING ON. IT'S SAFER FOR ME HERE, ARGUING WHICH WILL BE THE INITIAL THREE AND THEN OVER TO THE NEXT SIX TO NINE MONTHS WHAT IS ADDITIONAL ONES BUT THESE ARE MOSTLY PULLED FROM OTHER STUDIES, N HAYNES AND WIDE RANGE OF STUDIES SO THAT WE DON'T HAVE TO SPEND A TON OF MONEY TESTING THEM, THE QUESTION EXCEPT IN COMMUNITIES THAT HAVE NOT BEEN ASKED THOSE QUESTIONS AND WE'RE NOT TRYING TO INVENT NEW INSTRUMENTS AT THIS POINT. OF TIME WE MAY DEVELOP NEW INSTRUMENTS OR LIKELY YOUR ADVICE ABOUT WHAT ARE THE RIGHT INSTRUMENTS AND MEASURES TO CARRY FORWARD IN TIME. AND THE PARTICIPANTS WILL HAVE DASHBOARDS ON THEIR PROGRESS AND ACCRUED AT FIRST GETTING BETTER THINGS THAT CONTEXTUALIZE DATA FOR THEM. THESE ARE FUTURE MODULES THAT WE'RE LOOK AT, COGNITIVE TESTING GRIP STRENGTH, PHYSICAL ACTIVITY, SOME SOONER THAN LATER AND THIS IS QUITE FRANKLY DIRECT VOLUNTEER PATH GET SURVEY DATA FIRST, THE HEALTH PROVIDER DATA WILL GET HER DATA FIRST. THIS IS PART OF THE CHALLENGE, WE WANT EVERYBODY ACROSS THE STUDY REGARDLESS OF METHODOLOGY HOW THEY ARE BROUGHT IN TO HAVE CONSISTENT DATA BUT THE EXPERIENCE HOW DIFFERENT HEALTH PROVIDER ORGANIZATIONS ARE DOING THIS AND BE COMPARING THOSE METHODS AS WELL AS WE GO FORWARD IN TIME. VERY SIMPLE PHYSICAL EVALUATION TO HAVE BIOSPECIMEN COLLECTION FOR THIS FIRST ROUND, BLOOD PRESSURE BMI HEART RATE, HEIGHT AND WASTE CIRCUMFERENCE AND WEIGHT. 44-MILLILITERS OF BLOOD, WE HOPE THAT'S A RARE INSTANCE URINE AND 35ING AL LE QUATS ARE IN THE BIOBANK, AND COLLECTIONS AS WELL. WE WILL HAVE A LOT OF OPPORTUNITIES TO HELP US SHAPE WHAT FUTURE THINGS WE SHOULD DO FOR PHYSICAL EVALUATIONS AND BIOSPECIMENS BUT WE TRY TO KEEP IT SIMPLE, A DROP FROM SOME OF THE OTHER COHORT STUDIES AS A STARTING PLACE. EHR DATA FROM BOTH PATHS, JUST GIVES A SENSE OF TIME LINE, AS HEALTH PROVIDER ORGANIZATIONS WHO WON THE AWARDS HAD TO DO DATA SPRINTS WITH US AS PART TO SHOW THEY COULD SIT WITH EHR DATA AND GET INTO RESEARCH FORM. THE DRC HAS INVESTMENT TO CLEAN AND CONTEXT CHURLIZE THE DATA -- CONTEXTUALIZE THE DATA FOR THE ORGANIZATION FRAMEWORK. AND THE DIRECT VOLUNTEERS IS CRUDE, MANUAL AND THE FIRST PLACE BUT WE HAVE BEEN WORKING ON A PILOT WITH ALL OF THE MAJOR EHR VENDORS OF THINK FOR SCIENCE PROGRAM, FOR THOSE WHO ARE FAMILIAR WITH THE BLUE BUTTON, HOW WE MAKE IT SIMPLE TO SAY I WANT TO DONATE MY EHR DATA TO RESEARCH, NOT JUST OURS BUT OTHERS AND THOSE PILOTS ARE UNDERWAY RIGHT NOW AND KEEPING PRESSURE ON TO SCALE OUT IN A SHORT PERIOD OF TIME. SO LET ME WRAP UP BY SAYING WE'LL DO A SET OF RESEARCH QUESTION OR RESEARCH RESOURCE WORKSHOPS THAT WILL PILOT ONE SOON BUT DO A BUNCH AT ONCE IN THE FALL. I TALKED TO THE INSTITUTE AND CENTER DIRECTORS ABOUT THIS AND I WANTED TO PLANT THE SEED WITH COUNCIL AND INTRAMURAL EXTRAMURAL RESEARCHERS, WE'LL COME AND ASK YOU THREE BIG QUESTIONS. AND REALLY ORGANIZE WE WILL PRETEND THIS ENTIRE RESOURCE WAS JUST YOU CAN HAVE EVERYTHING YOUR WAY, RIGHT, NEAR TERM, WHAT ARE THE LOW HANGING FRUIT QUESTIONS AND MEASURES AND STRUMS TO ANSWER THOSE QUESTIONS, THAT SOMETHING TO SCALE OF ALL OF US IS GOING TO MOVE THE SCIENCE FORWARD, IT'S NOT THE RIGHT TOOLS FOR THE RIGHT JOB FOR OTHER KINDS OF THINGS, WHAT QUESTIONS MIGHT YOU WANT TO ANSWER BUT YOU NEED WORK SELECTING IDEA LOGICAL BATTLES BETWEEN HOW YOU'RE GOING TO COLLECT BLOOD PRESSURE OR SOMETHING MORE COMPLICATED THAN THAT BUT YOU HAVE A LINE OF SITE FIGURING THAT OUT AND LOCK TERM LONG TERM WHAT QUESTIONS ARE RIGHT FOR THE PROGRAM TO DECIDE AND YOU MAY NOT HAVE A CLUE HOW TO CAPTURE DATA TO GO THROUGH THAT. WE OOH HE WILL GO THROUGH THAT WITH MULTIPLE AREAS OF THOUGHT AND RESEARCH AND PULL OUT COMMON INGREDIENTs. WE WILL FUND WITH OUR BUDGET THE INGREDIENTS THAT SERVE SEVERAL SWIM LANES OF SCIENTIFIC THOUGHT AND THE REST WILL NEED TO BE FUNDED BY OUTSIDE PLAYERS, SOMETHING SPECIFIC TO AGING DOES NOT APPLY TO ANYTHING ELSE, LOOK AT WHETHER THAT MAKES SENSE IN DOING ANCILLARY STUDY SMALLER GROUP OR DOES IT MAKE SENSE TO DO IT IN A LARGER STUDY BECAUSE YOU NEED THE POWER OF A MILLION TO ANSWER THOSE QUESTIONS. THERE'S A WHOLE PROCESS WE'RE SETTING UP TO DO THAT BUT WE WANT TO START WITH RESEARCH QUESTIONS WORKSHOP, SOME WERE DONE WHEN THE ATV DID THE WORKING GROUP REPORT TO MAKE SURE WE'RE ON A PATH TO BUILD SOMETHING USEFUL BUT PRIORITIZES AND MAKES CHOICES TO SAY IF WE CAN'T BE EVERYTHING TO ALL PEOPLE IN EVERY RELEASE SO IMAGINE FOR EXAMPLE A DEEP FOCUSED END VERSION 2 AROUND MENTAL HEALTH AND AGING AND IT'S NOT THAT WE WOULDN'T HAVE OTHER MEASURES AND INSTRUMENTS BUT WE FOCUSED IN AND WANT PARTICIPANTS AND RESEARCH COMMUNITY TO KNOW HEY, V 2 IS ABOUT THESE AREAS, HELP DEFINE THAT WITH OTHER FUNDERS FROM THE INSIDE AND DELIVER AS WE GO FORWARD. SO I WILL LEAVE IT WITH THAT, I PROBABLY WENT TOO LONG AND DIDN'T LEAF TIME FOR QUESTIONS BUT THERE YOU GO. QUICK OVERVIEW STATUS REPORT OF ALL OF US RESEARCH PROGRAM. [APPLAUSE] >> WE'LL TAKE A QUICK COUPLE OF QUESTIONS. DR. SPECIALING WAS FIRST. >> REALLY INTERESTING. I WONDER WHAT YOU'LL DO ABOUT PARTICIPATION IN OTHER RESEARCH IN CLINICAL TRIALS BECAUSE PEOPLE WITH THE VOLUNTEER GENE MIGHT BE A GREAT OPPORTUNITY TO TAKE INFORMATION LIKE AMYLOID SCREENING WILL BE IN ABOUT 30,000 PEOPLE OVER THE NEXT TWO YEARS AND VARIOUS STUDIES. BUT MAY INTERFERE WITH YOUR DATA SO ARE YOU CAPTURING DATA ON WHAT OTHER STUDIES THEY'RE IN? >> WE ARE AND OTHER HEALTH PROVIDER ORGANIZATIONS HAVE THEIR OWN BIOBANK AND STUDIES, WE'RE TRYING TO NEGOTIATE WHAT PARTICIPANT BURDEN IS. YOU CAN'T DO ANY MORE RESEARCH REASONABLE POLICIES IS AROUND WHAT'S TOO MUCH BURDEN, ENJOY AT LEAST A WEEK BEFORE BRINGING SOMEBODY BACK IN FOR ANOTHER STUDY, CERTAINLY IT'S ONE OF THE GREAT POTENTIAL VALUE PROPOSITIONS IS TO MAKE SURE THIS IS SET UP TO BE ABLE TO DO CLINICAL TRIAL TARGETING WITH REALLY DEEP DATA ABOUT THIS GROUP OF PEOPLE. >> DR. RANDO. >> I WAS WONDERING IF YOU COULD TALK ABOUT THE AGE PROFILE FOR YOUR RECRUITMENT LIKE YOU WANT EVERYBODY WHO IS 18 AND OLDER FOLLOW FOR SIX YEARS OR ARE YOU GOING TO TAKE PEOPLE AGE 50 AND OVER AND FOLLOW THEM THROUGH THE LIFE SPAN? >> WE'RE WORKING THROUGH NOT BEING AN EPIPOPULATION, I'M HOPING TO HIRE A CHIEF MEDICAL OFFICER BUT HOPEFULLY THERE'S OHIO I SENT A NOTE TO DAVID MURRAY THE OTHER DAY, FOR THOSE THAT KNOW DAVID WE FOCUS ON RACE ETHNICITY AND NOW LOOKING AT SPECK TAIGS AROUND GENDER, AGE AND ALL OF THAT. I DON'T WANT TO GET INTO A GOURDION KNOT OF UNRECRUITIBILITY. THINKING OF ISSUE OUR SCIENTIFIC GROUP IS, WALKING THROUGH IN MORE DETAIL SO I DON'T KNOW WHAT THE NUMBERS WILL BE, AND LAUNCH WE'RE DOING 18 AND ABOVE AND THERE'S NO RESTRICTIONS. BEYOND THAT. WE'RE NOT READY FOR COGNITIVELY IMPAIRED, WE HAVE A WORK GROUP KIRKING OFF ON WORK GROUP CHILDREN AND PREGNANT WOMEN ALLOWED IN THE STUDY, WE'RE WORKING TOWARDS ADDING THINGS LIKE FAMILY RECRUITMENT AS WELL AS WE HAVE COMMITTED TO DOING CHILDREN AND THOSE COGNITIVELY CHALLENGED AND INCARCERATED. ONE THING THAT'S HURTING US IS STATE BY STATE VARIABILITY AROUND ISSUES AND HOW TO NAVIGATE THAT. WE'RE WORKING THROUGH THOSE ISSUES AND BUT WE EXPECT AND WANT -- WE HAVE TO FIGURE OUT ALL THE MAPS, WHAT ARE EXPECTATIONS ABOUT THOSE WHO WILL DROP OUT OR DIE AND HOW DO WE REDEGREES SO WE DON'T HAVE IT NEATLY FIGURED OUT, THERE IS A LITTLE TWEAKING OF SOME OF THE QUESTIONNAIRES EVEN LAUNCH IN TERMS OF THOSE -- I FORGET THE CUT OFF, 80 AND ABOVE OR 65 AND ABOVE. PART OF THE CHALLENGE, ON THE CHILDREN SIDE IS WE'RE NOT FUNDED TO BECOME NATIONAL CHILDREN STUDY PART 2 BUT WE OBVIOUSLY ONCE INCLUDE 18 AND UNDER, AS YOU THINK ABOUT THOSE 55 AND ABOVE AND THE OLD, WE WANT SOME MODULES THAT ARE INTELLIGENTLY ANTICIPATING FUTURE AGE AS WELL AS ONCE THEY REACH MARKS ADDING ADDITIONAL CAPABILITY TO COLLECT ADDITIONAL DATA YOU WOULDN'T ON THE OTHER. WE'RE TRYING TO BE PURE AS WE START BUT IT'S MORE PRACTICAL ISSUES OF HOW WE RECRUIT THE FOLKS AND DEAL WITH LEGAL AND ETHICAL ISSUES. >> DR. RANDO. >> I HAVE A QUESTION, A MODEL PARTNERS WE ARE IN THE PROCESS OF RECRUITING ANOTHER MILLION PEOPLE, ARE YOU THINKING YOU WILL INTEGRATE WITH RECRUITMENTS IN THESE LARGE FACILITIES OR HAVE IT SEPARATE? >> IN MOST CASES IT'S SEPARATE EVEN IN THE VA, SO MIKE (INAUDIBLE) WAS PART OF THE WHOLE ACD WORKING GROUP AND ADVISORY PANEL UNTIL WE GAVE AWARD TO BE BASICALLY HEALTH PROVIDERS ORGANIZATION FOR US. CHRIS O'DONNELL ON THE EXECUTIVE COMMITTEE, INITIALLY RECRUITING FOLKSS FROM THE MVP BUT IT'S A SEPARATE RECRUITMENT AND SEPARATE INSTANCE WHEN THEY ACTUALLY COME IN. AND WE'RE TRYING TO KEEP THINGS PRETTY SEPARATE AT THE BEGINNING, EVEN FOR OTHERS WHO ARE PULLING FROM A LOCAL BIOBANK. I BELIEVE ULTIMATELY WE WILL GET MORE COMFORTABLE WITH THE IDEA OF ONE VISIT TO ONE BLOOD DRAW THAT SUPPORTS BOTH BUT WE'RE NOT STARTING THAT WAY TO THE CHAGRIN OF HEALTH PROVIDER ORGANIZATIONS BUT THE COVENANT AND COMMITMENT PROTECTING PEOPLE DATA WE'RE MAKING AT FEDERAL GOVERNMENT, AND POTENTIAL FOR CONFUSION AROUND THAT STUDY, WE'RE KEEPING THEM ISOLATED RORRIE CONTROL RINSE FROM THE UK BIOBANK IS ON ADVISORY PANEL AS WELL. AMONG THOSE THREE WE'RE TRYING TO SHARE BEST PRACTICES AND TALK COMPARABILITY ACROSS THE DATA SETS AND WHAT WE DO TO FACILITATE THAT OVER TIME. HIRO, THE HEADS OF INTERNATIONAL RESEARCH ORGANIZATIONS AND SURVEYS SEEN THERE ARE 59 COHORTS OF 100,000 OR MORE SO THERE'S A CONVENING OF THAT, A MILLION IS NOT NEARLY ENOUGH FOR CERTAIN KINDS OF RESEARCH QUESTIONS TO THINK ABOUT CROSS COHORT COMPARISON AS WELL. >> THANK YOU VERY MUCH, DOCTOR. >> THANK YOU. >> OUR NEXT SPEAKER IS DR. KEN LANGI WHO WILL BE INTRODUCED BY DR. JOHN KING. >> REALLY BRIEFLY, YOU CAN READ ALL OF KEN'S AWESOME TITLES UNIVERSITY OF MICHIGAN ON A SHEET. IN ADDITION TO THOSE ALSO LISTED RESEARCH PROFESSOR AND SURVEY RECENTER AND (INAUDIBLE) AND MICHIGAN ALZHEIMER'S DISEASE FOUNDER. HIS BACHELOR IS IN -- BACHELOR IS IN SOCIOLOGY FROM AM HE IS COLLEGE AND UNIVERSITY OF CHICAGO. HE WILL TALK ABOUT PROJECT THAT GOT INTERESTING PRESS BACK IN NOVEMBER INCLUDING WHAT FOR MANY OF US IN THE DC AREA IS THE MIC DROP MOMENT APPEARING ON THE DIANE RING SHOW. THAT'S STILL ON NEW BUCKET LIST, SORRY THE HEAR ABOUT THAT. WITHOUT FURTHER ADIEU. KEN. >> THANKS, JOHN. GET MY SLIDES GOING HERE. THANK YOU, JOHN, THANKS TO MY FRIENDS IN BSR FOR INVITING ME WHAT WE HAVE BEEN DOING WITH THE HEALTH AND RETIREMENT STUDY. I HAVE NO CONFLICTS OF INTEREST. SO AS JOHN SAID WE'LL TELL YOU A PAPER WE HAVE DONE PUBLISHED RECENTLY ACKNOWLEDGING MY CO-AUTHORS, ERIC LARSON, FROM SEATTLE, GENOMIC COUNCIL AND OTHER COLLEAGUES FROM THE UNIVERSITY OF MICHIGAN, PI WHO DID RETIREMENT STUDY AND THANKS VERY MUCH TO FUNDING FROM NIA, MULTIPLE DIFFERENT WAYS, THIS IS THE HEALTH RETIREMENT STUDY GRANT AND THEN CAREER AWARDS TO -- AND ALSO ACKNOWLEDGING THE SOCIAL SECURITY ADMINISTRATION THAT HELPS FUND THE HRS. SO WHAT I WILL DO TODAY IN THE NEXT 20 MINUTES OR SO IS A QUICK BACKGROUND ON DEMENTIA ALZHEIMER' DISEASE, A LITTLE BIT ABOUT THE TRENDS GOING ON IN THE POPULATION THAT WE THINK ARE ACTING BRAIN HEALTH FOR GOOD AND BAD. I WILL TELL YOU ABOUT THE HEALTH RETIREMENT STUDY IN THIS SPECIFIC ANALYSIS THAT WE HAVE DONE AND THEN SOME CONCLUSIONS AND THINGS WE'RE PLANNING TO DO NEXT WITH NIA'S HEALTH IN TERMS OF UNDERSTANDING COGNITION AND TRENDS IN DEMENTIA HERE AND AROUND THE WORLD ACTUALLY. SO QUICKLY JUST TO GET EVERYONE ON THE SAME PAGE, ACCORDING TO THE NIA AND ALZHEIMER'S ASSOCIATION, THESE CRITERIA TO DIAGNOSE DEMENTIA, IMPAIRMENT IN AT LEAST TWO COGNITIVE AREAS, MEMORY, REASONING AND YOU SEE THE OTHERS THERE. AND THEN THAT -- THOSE IMPAIRMENTS ARE SUFFICIENT ENOUGH FOR SEVERE ENOUGH TO CAUSE INTERFERENCE WITH THE ABILITY TO FUNCTION AT WORK. USUAL ACTIVITIES IN OTHER WORDS CREATE DISABILITY PEOPLE ARE NO LONGER ABLE TO GET THROUGH THE DAY, INDEPENDENTLY. OF COURSE, THAT IS A DIFFICULT AND FUZZY BORDER WHICH CREATES UNCERTAINTIES ABOUT MAKING DEMENTIA DIAGNOSIS IN CLINICAL AND POPULATION BASED STUDIES, WE WILL TALK ABOUT THAT IN A BIT. THE CAUSES OF DEMENTIA AS MANY OF YOU KNOW, ALZHEIMER'S DISEASE, BUILD UP OF AMYLOID AND INFLAMMATION THAT CAUSES -- THOUGHT TO CAUSE, 70% OF CASES, VASCULAR ISSUES WITH ATHEROSCLEROTIC BLOOD FLOW PROBLEMS, STROKES AND ANOTHER 20 TO 30%, RARER CAUSES, OF DEMENTIA, LISTED HERE. AS YOU KNOW THIS IS PROBABLY A TOO SIMPLISTIC VIEW OF DEMENTIA AND CAUSES FOR DEMENTIA. AUTOPSY WORK IN NEUROPATH WORKs IS WILL BELIEVE I POPULATION BASED LIKE INDEPENDENT STUDY OVER THE LAST 20 YEARS OR SO HAVE SHOWN MIXED DEMENTIA SO MOST PEOPLE, ADULTS 85 AND OLDER HAVE MULTIPLE PATHOLOGIES IN THEIR BRAIN OVERLAPPING ALZHEIMER'S DISEASE, SCREWS LAR DISEASE LOU WII BODY SO A VASTLY COMPLEX PICTURE THAN THE LIST AT THE TOP SHIFTS. AND AGAIN, THIS CONNECTION BETWEEN ALZHEIMERS DISEASE AND CARDIOVASCULAR RISK FACTORS AND VASCULAR PATHOLOGY IS IMPORTANT AND WILL BE A THEME RUNNING THROUGH THE TALK. SOME OTHER WAYS WE THINK THAT ALZHEIMER'S AND CARDIOVASCULAR RISK FACTORS, DISEASE OVERLAP AND INTERACT THROUGH RISK FACTORS, HYPERTENSION, CHOLESTEROL, OBESITY, DIABETES, PHYSICAL INACTIVITY, SMOKING YOU CAN SEE THE LIST THERE. SO CLASSIC CARDIOVASCULAR RISK FACTORS STEAM TO INCREASE -- SEEM TO INCREASE RISK FOR ALZHEIMER'S DISEASE AND MIXED DEMENTIA. LOTS OF INTERESTING AND COMPLEX ISSUES AROUND WHAT TIME OF LIFE THESE RISK FACTORS ARE MOST ACTIVE SO IS IT MID LIFE HYPERTENSION HIGH CHOLESTEROL THAT ARE IMPORTANT IN LATER LIFE, WORK GOING ON INTERNET AND OTHER STUDIES TRYING TO SORT THAT VERY IMPORTANT PICTURE AND WE WILL TALK ABOUT THAT. CLINICALLY, PATHOLOGICALLY FOR A GIVEN LEVEL OF ALZHEIMER'S PATHOLOGY, THE MORE VASCULAR LESIONS THE MORE LIKELY SOMEBODY HAS CLINICALLY SIGNIFICANT COGNITIVE IMPAIRMENT OR DEMENTIA. QUICKLY, WE THINK DEMENTIA IMPORTANT, THE NUMBER OF PEOPLE WITH THE PREVALENCE OF DEMENTIA AND ALZHEIMER'S DISEASE AND ECONOMIC IMPACT LED MY MIKE HEARD A FEW YEARS AGO SHOWING THAT THE PUNCH LINE WAS $50,000 PER CASE OF DEMENTIA IN THE UNITED STATES AND THAT'S THE SO CALLED MARGINAL COST, FOR OTHER CHRONIC DISEASES THAT COST 200 BILLION NATIONWIDE NOT SURPRISING TO THIS GROUP HERE BUT THE MAIN IMPACT OF ALZHEIMER EASE DISEASE IS REALLY ON THE FAMILY -- THE INFORMAL CARE CAUSE THOUGHTS TO MAKE UP 50% OF THE IMPACT, ECONOMIC IMPACT OF DEMENTIA, ANOTHER QUARTER OF LONG TERM CARE IN NURSING HOLMES. ALL RIGHT. SO TURNING TO THESE RECENT TRENDS THAT WE THINK ARE IMPORTANT TO BRAIN HEALTH. THERE'S INCREASE IN PREVALENCE OF OBESITY DIABETES AND HYPERTENSION, THESE RISK FACTORS WERE WE THINK IMPORTANT BUT AT THE SAME TIME OVER 20 YEARS THERE'S MUCH MORE WIDESPREAD INTENSIVE TREATMENT OF THESE RISK FACTORS, DON'T HAVE TIME TO GO THROUGH THE EVIDENCE HERE BUT AROUND THE WORLD SYSTOLIC BLOOD PRESSURE IS COMING DOWN, A MILLIMETER OF MERCURY PER DECADE OVER THE LAST FEW DECADES, LOWER -- BETTER CONTROL OF DIABETES AND HIGH CHOLESTEROL, STILL A LONG WAY TO GO IN TERMS OF GETTING EVERYONE CONTROL BUT THERE'S BEEN SIGNIFICANT IMPROVEMENTS, MY FAVORITE GRAPH SHOW SOME OF THESE IMPROVEMENTS IN VASCULAR RELATED RISK FACTORS WITH A PAPER FROM A FEW YEARS AGO 2014 LOOKING JUST AT THESE ARE VASCULAR DIABETES AND TRENDS IN THEM, YOU CAN SEE THIS INCREDIBLE DECLINE IN FOR INSTANCE HEART ATTACKS, 75% RELATIVE DECLINE, THESE ARE EVENTS PER 10,000 PEOPLE WITH DIABETES IN THE UNITED STATES. HUGE DECLINE IN STROKES AND MUTATIONS LESS SIGNIFICANT IN KIDNEY DISEASE. THE TAKE AWAY IS SOMETHING IS GOING ON IN VASCULAR HEALTH, THESE ARE IMPROVED, JUST IN DIABETICS BUT BY EXTENSION PERHAPS THIS IMPROVEMENT IN VASCULAR HEALTH IS IMPROVING BRAIN HEALTH AND DECREASING DEMENTIA RISK OVER THE NEXT 25 YEARS OR SO. THE OTHER HUGE IMPORTANT TREND WE THINK IS THIS BOOM IN EDUCATION. THIS IS DATA SHOWING RISE IN THE FRACTION OF 30 TO 34-YEAR-OLDS WITH COLLEGE EDUCATION, LOWER INCOME COUNTRIES HERE UP THROUGH 2010, HIGHER INCOME COUNTRIES HERE, YOU CAN SEE IN BOTH LOWER AND HIGHER INCOME COUNTRIES THIS TREND TOWARD INCREASING LEVELS OF EDUCATIONAL ATAPEMENT PEOPLE GOING TO SCHOOL, MORE YEARS OF FORMAL EDUCATION, AROUND THE WORLD. THE OTHER END OF THE EDUCATION SPECTRUM LITERACY ALSO INCREASING SIGNIFICANTLY AROUND THE WORLD SO PEOPLE ARE CHALLENGING THEIR BRAINS MORE, IT SEEMS, ON AVERAGE, GROWING UP OVER THE LAST 40 YEARS, AS MANY OF YOU KNOW, WE THINK EDUCATION IS IMPORTANT FOR BRAIN HEALTH, INTERESTING TO SHOW THOSE NUMBERS IN THE U.S., 53% OF PEOPLE FINISHED HIGH SCHOOL IN 1990, UP TO 80% IN 2010, SIMILAR INCREASES IN FINISHING COLLEGE. WE THINK EDUCATION IS PROTECTIVE FOR PROBABLY LOTS OF COMPLICATED AND OVERLAPPING AND BIODIRECTIONAL WAYS BUT IMPORTANT AS WE THINK IS THIS IDEA OF COGNITIVE RESERVE, THE IDEA THAT CHALLENGING YOUR BRAIN FROM BIRTH ADOLESCENCE AND OLDER AGE YOU ARE CHANGING THE BIOLOGY OF THE BRAIN CREATING MORE THAN NETWORK CONNECTIONS AMONG NEURONS TO COMPANY SIT FOR AGE RELATED PATHOLOGIES AND CONTINUE TO THINK -- COMPENSATE FOR AGE RELATED PATHOLOGY AND THINK NORMALLY AND NOT HIT THE DEMENTIA THRESHOLD BEFORE ONE DIES SO DECREASING RISK. SO OBVIOUSLY EDUCATION, MORE EDUCATED PEOPLE SMOKE LESS, THEY HAVE OCCUPATIONS THAT KEEP BRAINS MORE CHALLENGED WITH COMPLEX IDEAS THROUGH THEIR LIFE, THEY DO DIFFERENT THINGS WITH DIFFERENT SOCIAL NETWORKS. SO AGAIN, IF THIS IS TRUE, NOT COGNITIVE RESEARCH BUT THINGS THAT LEADS TO BETTER BRAIN HEALTH. TO SUMMARIZE THAT IN AN INTERESTING PAPER BY NORTON AND COLLEAGUES IN 2014 TO END UP THESE MYOCARDIAL RISK FACTORS, DEPRESSION AND ESTIMATED 30% OF ALZHEIMERS AND DEMENTIA CASES WORLDWIDE ARE ATHEREABOUTED TO THE MODIFIABLE RISK FACTORS SO IF WE ADDRESS THESE BY EXTENSION, WE CAN LEAD TO PREVENTION OF SIGNIFICANT NUMBER OF DEMENTIA CASES. WITH THAT AS BACKGROUND TURNING SPECIFICALLY TO THE OPEN RETIREMENT STUDY, WHAT WE WERE TRYING TO UNDERSTAND IS WHAT WAS THE TREND IN DEMENTIA PREVALENCE BETWEEN 2000 AND 2012, AND FOR THOSE WHO DON'T KNOW THE HRS ONGOING REPRESENTATIVE LONGITUDINAL STUDY, ABOUT 20,000 AMERICANS OVER THE AGE OF 50 INSTITUTE FOR SOCIAL RESEARCH UNIVERSITY OF MICHIGAN FUNDED BY NIA AND SOCIAL SECURITY ADMINISTRATION SINCE THE EARLY 1990s DAVID W,IR IS -- WIER, WE STARTED COLLECTING LOTS OF DATA ABOUT DIFFERENT ASPECTS OF LIFE, I WILL TELL YOU MORE ABOUT THAT SPECIFICALLY, HALF OF THE INTERVIEWS ARE DONE FACE TO FACE STARTING IN 2006 AND HAVE BY TELEPHONE ALL DATA ARE MADE PUBLIC SO THERE'S PUBLICATIONS BY LOTS OF REGISTERED DATA USES, 15,000 AROUND THE WORLD, MANY AUTHORS WERE NOW IN 2016, ABOUT -- UP TO 180 PAPERS PER YEAR PUBLISHED WITH HRS SO EVERY TWO DAYS INSURANCE PAPER WAS PUBLISHED, HERE IS THE SURVEY CONTENT MORE SPECIFICALLY KIND OF DATA WE COLLECT BOTH BY SURVEYS IN ERIC DISHMAN'S PRESENTATION THAT WE HAVE DIFFERENT KINDS OF DATA STREAMS, WE DO A SURVEY SORT OF CLASSIC INTERVIEWER BASED SURVEY TO GATHER LOTS OF SELF-REPORTED INFORMATION THAT YOU CAN SEE HERE INCLUDING PHYSICAL AND FUNCTIONAL HEALTH PERFORMANCE BASED COGNITIVE TESTING, I WILL TELL YOU MORE ABOUT ESPECIALLY RELEVANT TO TALK TODAY LOTS OF RELEVANT INFORMATION. WE DOD A MINUTE STRAYTIVE LINKAGES -- ADMINISTRATIVE WITH MEDICARE, THE NATIONAL DEBT INDEX TO LINK DATA WITH THE VA HEALTHCARE SYSTEM WHICH WE HAVE BEEN DOING FOR THE LAST SIX OR SEVEN YEARS, BUMPS ALONG THE WAY BUT GETTING THE VA DATA OUT TO LINK TO SOCIAL SECURITY ADMINISTRATION. WE COLLECT BIOMARKERS BY DRY BLOOD SPOT IN 2006, DR. CRIMMINS IS LEADING OUR BIOEFFORT IN 2016, WE'RE DOING INTRAVENOUS BLOOD COLLECTION, LOTS OF ADDITIONAL SERUM BIOMARKERS INCLUDING INFLAMMATORY BIOMARKERS THAT EXPAND WHAT CAN BE DONE WITH BIOMARKER RESEARCH WITH HRS. WE GENOTYPED 20,000 PEOPLE WITH TWO AND A HALF MILLION SNP CHIP. SPECIFICALLY AROUND TRACKING COGNITION AND BRAIN HEALTH WE USED THE MODIFIED VERSION OF THE TELEPHONE INTERVIEW FOR COGNITIVE STATUS WHICH IS A MINI MENTAL STATE EXAM DONE ON THE PHONE, YOU CAN SEE QUESTIONS HERE, WE ALSO HAVE VERBAL FLUENCY NUMBER OF QUESTIONS, PROXIES ARE IMPORTANT WHEN STUDYING COGNITIVE DECLINE AND IMPAIRMENT. WE HAVE A NUMBER OF PROXY INSTRUMENTS THAT FOR PEOPLE THAT AREN'T ABLE TO ANSWER THE SURVEY THEMSELVES PROVIDE INFORMATION ABOUT HOW PEOPLE ARE FUNCTIONING COGNITIVELY AND PHYSICALLY. WE ASK ABOUT WHETHER THEY HAVE BEEN HAD A DOCTOR WORK UP OR DOCTOR DIAGNOSED DISEASE AND IN TERMS OF PROTECTIVE RISK FACTORS WE COLLECT A BUNCH OF INFORMATION ABOUT CARDIOVASCULAR RISK, WE MEASURE BLOOD PRESSURE, ET CETERA, WE HAVE LOTS OF INFORMATION ABOUT ACUTE MEDICAL EVENTS THAT AFFECT COGNITION FROM OUR LINKAGE TO MEDICARE DATA AND EDUCATION AND THESE OTHER THINGS HERE. AS A SUBSTUDY TO HRS THE NIA FUNDED THIS AGING DEMOGRAPHIC AND MEMORY STUDY OR ATOMS BACK IN EARLY 2000S TO GET A DEEPER DIVE ON COGNITION AND COGNITIVE FUNCTION AND DEMENTIA, WE WENT TO HOLMES OF 850 PEOPLE AND VERY IN DEPTH ASSESSMENT AND THEN GAVE THAT INFORMATION TO A CONSENSUS PANEL THAT MADE A DIAGNOSIS USING THAT INFORMATION COGNITIVE IMPAIRMENT WITHOUT DEMENTIA AS WELL AS CAUSE. WE VIEW THAT AS OUR GOLD STANDARD DIAGNOSIS OF DEMENTIA CLOSE TO HAPPEN IN CLINIC AS POSSIBLE AND USE THAT INFORMATION ON THIS SMALLER SAMPLE TO TRY TO UNDERSTAND THE PROBABILITY OF DEMENTIA FOR THE REST OF THE SAMPLE IN THE HRS WE DO THAT RELATIVELY STRAIGHT FORWARD WAY, A NUMBER OF PEOPLE HAVE DONE IT IN DIFFERENT WAYS BUT THIS IS ONE WAY, FINDING CUT POINTS ON HRS COGNITIVE AND OTHER MEASURES IN WAYS THAT LINES UP WITH THE ATOMS GOLD STANDARD DIAGNOSIS AND PREVALENCE ESTIMATES THERE. SO WE USE THIS TICKS AND PROXY INFORMATION TO PHUT PEOPLE IN THE BENDS OF DEMENTIA OR CIND OR NORMAL AND CONCORDANCE WITH THIS LIMITED AMOUNT OF INFORMATION OR THESE LIMITED DATA HERE IS ALMOST 80% WITH THE ATOMS DEMENTIA DIAGNOSIS. SO FOR THIS SPECIFIC STUDY WHAT WE TRIED TO DO IS USE THOSE DEMENTIA DIAGNOSES OR ASSESSMENTS FROM THE SAMPLE 65 AND OLDER. WE LOOKED AT THE 2000 SAMPLE AND THE 2012 SAMPLE, PULLED THAT DATA AND DID REGRESSION MODEL, WITH ONE VARIABLE INDICATING WHAT WAS 2000 OR 2012, JUST AND THE CO-EFFICIENT ON THAT VARIABLE LETS US UNDERSTAND HAS THERE BEEN A DECLINE IN DEMENTIA PREVALENCE THE ODDS IN THE 65 PLUS POPULATION BETWEEN THE TWO TIME POINTS THEN WE HAD EXPLORATORY VARIABLES LIKE CARDIOVASCULAR RISK LIMITED TO TRY TO UNDERSTAND HOW THOSE VARIABLES OR FACTORS HOW THEY MAY HAVE AFFECTED DEMENTIA RISK AND PREVALENCE. JUST TURNING TO THE RESULTS, IN 2000 WE HAD ABOUT 10,500 PEOPLE IN THE 65 MUSS SAMPLE, SIMILAR NUMBER IN 2012, AGE WAS SIMILAR THOUGH THERE WAS A LARGER FRACTION OF 85 PLUS AGED FOLKS IN 2012, WHICH IS IMPORTANT FOR DEMENTIA SINCE THEY'RE AT THE HIGHEST RISK. HERE IS THIS BIG INCREASE IN EDUCATION THAT SHOWS UP AS A MEAN INCREASE OF ALMOST A YEAR OF EDUCATION LEVEL BETWEEN 2000 AND 2012. ALSO INCREASE IN NET WORTH, THESE ARE ADJUSTED FOR INFLATION, $2,000 WITH INCREASE IN NET WORTH AMONG 65 PLUS POPULATION ALSO. IN TERMS OF CARDIOVASCULAR RISK FACTORS AND DISEASE, STROKE HISTORY OF STROKE DROPPED SLIGHTLY BUT NOT STATISTICALLY SIGNIFICANTLY AND THE LARGE INCREASE IN DIABETES, SMALLER INCREASE IN DIAGNOSED HEART DISEASE, AND HYPERTENSION AND OBESITY. THIS WAS THE MAIN PUNCH LINE OF THE STUDY THAT WE FOUND IN 2000, 11.6 PEST OF THE 65 PLUS SAMPLE MET THIS DEMENTIA CLASSIFICATION, DEMENTIA DIAGNOSIS DOWN TO 8.8% IN IS 2012, SIGNIFICANT DECLINE TOTAL PREVALENCE IN THE 65 PLUS POPULATION. HERE IS STRATIFIED BY AGE GROUP WITH DECLINE SIGNIFICANT DECLINES REALLY ACROSS THE AGE RANGE FROM 65 AND OLDER. HERE IS THE RESULT OF THE REGRESSION ANALYSIS A LITTLE HARD TO SEE BUT WANT TO POINT OUT A FEW ISSUES OR FEW SPECIFIC FINDINGS HERE, THE FIRST ROW SHOWS THE TREND VARIABLE THESE ARE THE -- THIS IS THE ODDS RATIO OF DEMENTIA IN 2012 VERSUS 2000 SO YOU CAN SEE LESS THAN ONE THERE'S A SIGNIFICANT DECLINE IN DEMENTIA ACROSS THAT TIME. THEN START TRYING TO UNDERSTAND DIFFERENCES ACROSS THE COHORTS IN AGE AND EDUCATION AND OTHER THINGS AFTER ADJUSTING FOR AGE AND SEX YOU CAN SEE DECLINE IS SLIGHTLY GREATER, THAT'S BECAUSE AGAIN THAT 85 PLUS POPULATION IN THE LATER COHORT WAS GREATER AND THERE ARE WHEN YOU ADJUST FOR THAT, YOU CAN SEE THAT MORE. EDUCATION LEVEL ONCE WE ADD THESE VARIABLES THAT SIGNIFICANT PROTECTIVE EFFECT FROM YEARS OF EDUCATION REFERENCES FOLKS WITH LESS THAN HIGH SCHOOL EDUCATION UP TO GREATER THAN COLLEGE OR COLLEGE OR MORE SO SIGNIFICANT PROTECTIVE EFFECTIVE EDUCATION NET WORTH IN TERMS OF RACIAL DIFFERENCES, EVEN AFTER ADJUSTING FOR AGE AND NET WORTH, AFRICAN AMERICANS SIGNIFICANTLY MORE LIKELY TO BE WITH DEMENTIA AS WELL AS HISPANIC INDIVIDUALS ALSO SO INCREASED RISK RELATED TO RACE AND ETHNICITY THERE. FINALLY ADJUSTING CARDIOVASCULAR RISK AND OBESITY, YOU CAN SEE STROKE AND DIABETES INCREASED RISK OF DEMENTIA INTERESTING HEART DISEASE SHOWS UP AS PROTECTIVE, WE THINK COMPLEX ISSUE AND IN FACT HEART DISEASE RELATIONSHIP DECLINE SIGNIFICANTLY BETWEEN 2000 AND 2012 IN AN INTERACTION, BY THAT I MEAN 2000 IT DIDN'T LOOK TO BE AS PROTECTIVE OR SIGNIFICANTLY PROTECTIVE BY 2012 IT DID AND WE THINK MAYBE RELATED TO THIS INCREASED INTENSITY OF TREATMENT OF CARDIOVASCULAR RISK FACTORS IN HEART DISEASE. JUST TO PUT THESE FINDINGS IN CONTEXT WHAT'S GOING ON IN THE LITERATURE RIGHT NOW, THERE'S INCREASING NUMBER OF POPULATION BASED STUDIES THAT HAVE BEEN FINDING THIS DECLINE IN PRECEDENCE OR INCIDENCE IN COGNITIVE IMPAIRMENT OR DEMENTIA, NATIONAL LONG TERM CARE STUDY BACK IN 2005 PUBLISHED RESULTS, WE HAVE TWO STUDIES FROM THE HEALTH RETIREMENT STUDY LOOKED EARLIER WAVES FROM 1993, 2002 AND FOUND A SIMILAR DECLINE MANY OF YOU IN THIS FIELD HAVE HEARD ABOUT THE CFAS STUDY IN ENGLAND ALSO PUBLISHED OVER THE LAST FEW YEARS THEIR DATA FROM ENGLAND THAT SHOWED DECLINE IN EVIDENCE AND INCIDENCE IN DEMENTIA, THE FRAMINGHAM STUDY EARLIER THIS YEAR IN NEW ENGLAND JOURNAL SHOWING DECLINE IN INCIDENCE FRAMINGHAM COHORT, UP TO ABOUT 20% PER DECADE OVER FOUR DECADES OR SO, ANOTHER PAPER IN PRESS USING THE AMERICANS CHANGING LIVES STUDY AND OTHER COHORT IN MICHIGAN THAT FOUND A SIMILAR STUDY. DENNIS EVANS HEALTH AND AGING PROJECT IN CHICAGO PUBLISHED THEY DIDN'T SEE A SIGNIFICANT DECLINE IN INCIDENCE, THE POINT ESTIMATE WAS GOING IN THAT DIRECTION BUT DIDN'T STATISTICAL SIGNIFICANCE. JUST TO END ON WHY THIS COMPLICATED TO DO, AND SEE SOME DIFFERENCES IN LITERATURE BECAUSE OF THE COMPLEXITIES TRYING TO UNDERSTAND MOVING IN THE POPULATION, TO ME ONE OF THE MOST IMPORTANT ISSUES IS THIS FUZZY THRESHOLD FOR THE DEMENTIA DIAGNOSIS, WHEN SOMEONE HIT THE DISABILITY CRITERIA, THAT'S GOING TO BE IMPORTANT IN UNDERSTANDING DIFFERENCES ACROSS STUDIES AND UNDERSTANDING CHANGES OVER TIME. ALSO CHANGES IN RESPONSE RATES TO SURVEY, CODING DIAGNOSES ADMINISTRATIVE DATA, THRESHOLD OF NURSING HOME ENTRY, ALL THESE THINGS HAVE IMPORTANT IMPACT ON WHAT THE PRE-LENS OR WHAT YOU'RE SEEING IN THE POPULATION. ALSO JUST FROM A PUBLIC HEALTH PERSPECTIVE IT'S ALSO IMPORTANT TO KNOW HOW LONG INDIVIDUALS ARE LIVING WITH DEMENTIA, IMPORTANT TO KNOW WHAT PROPORTION OF THE POPULATION HAS DEMENTIA OF ANY POINT IN LIFE WHAT PREVALENCE IS, BUT AGAIN, I THINK WHAT WE WANT TO KNOW IS HOW LONG ARE PEOPLE LIVING WITH IT, WHAT'S THE BURDEN TO SOCIETY, WHAT'S THE COGNITIVELY HEALTHY LIFE EXPECTANCY SO TO SPEAK AND LUCKILY EILEEN CRIMMINS DID COMPLICATED WORK TO TRY TO UNDERSTAND THIS WITH THE HRS IN A PAPER PUBLISHED RECENTLY IN MEDICINE, THIS IS SHOWING PERSPECTIVE WITHTY MEN SHAH IN DECEMBER 2010, PEOPLE AT AGE 65, FOR THEIR REMAINING LIFE EXPECTANCY AT AGE 65, WHAT I MEAN COLLEAGUES FOUND WAS THAT THE PERCENTAGE OF LIFE LIVED OR EXPECTED TO BE LIVED DEMENTIA IN 2000 WAS 11.2%, DROP TO 7.9% IN 2010, SO A DROP OF 3.3 PERCENTAGE POINTS, SIMILAR PATTERNS THIS IS FOR MEN, WOMEN, AT AGE 85, SIMILAR PATTERNS HERE, WE'RE DECREASED EXPECTED AMOUNT OF TIME IN REMAINING LIFE. IN DEMENTIA WHICH IS GOOD NEWS. SO CALLED COMPRESSION OF MORBIDITY THAT PEOPLE ARE SPENDING LESS. THOUGH LIFE EXPECTANCY INCREASING SPENDING LESS TIME WITH COGNITIVE IMPAIRMENT DEMENTIA. JUST TO END WITH SOME OF THE THINGS THAT WE'LL BE DOING GOING FORWARD, NIA HAS ENCOURAGED US AND TO DEVELOP THIS NEW HARMONIZED COGNITIVE ASSESS T PROTOCOL WE HAVE BEEN WORKING ON OVER THREE OR FOUR YEARS WITH COLLEAGUES I MENTION, SO WHAT THIS IS AN HOUR NEUROPSYCHOLOGY ASSESSMENT WE'RE ADMINISTERING TO 3,000 HRS RESPONDENTS SO NOT AS DETAILED AS ADAMS BUT WE'RE DOING IT IN A MUCH LARGER SAMPLE, WE THILL THIS RICHER ASSESSMENT WILL IMPROVE INDICATION OF EARLY COGNITIVE DECLINE, ALLOW MORE SPACE FOR DIAGNOSES AND ALSO COLLABORATING AND LOOKING AT INTERNATIONAL DIFFERENCES IN COGNITIVE IMPAIRMENT AND DEMENTIA ACROSS A NUMBER OF COUNTRIES, THIS AGE GAP ASSESSMENT WAS DEVELOPED IN COLLABORATION WITH NUMBER OF ONGOING STUDIES INCLUDING THE BENNETT STUDY IN CHICAGO, THE CFAS IN 10 66 STUDIES TO GET VALID COMPARISONS ACROSS STUDIES IN THE UNITED STATES AND ACROSS COUNTRIES ACROSS THE WORLD. SO WE THINK THIS WILL INCREASE OPPORTUNITIES TO STUDY TRENDS AND INTERNATIONAL COMPARISONS OF PREVALENCE. SO TO CONCLUDE WE THINK THAT WE FOUND DEMENTIA PREVALENCE DECLINED IN THE UNITED STATES BETWEEN 2000 AND 2020 IN LINE WITH RECENT FINDINGS FROM FRAMINGHAM, ENGLAND AND OTHER HIGH INCOME COUNTRIES. IT SEEMS THAT RISING LEVELS OF EDUCATION AND PERHAPS COGNITIVE RESERVE IN THE MORE BORING COHORTS IS CONTRIBUTING TO THIS DECLINE IN AGE SPECIFIC DEMENTIA RISK IN BETTER CONTROL CARDIOVASCULAR RISK FACTORS WE THINK IS PART OF THIS STORY, BUT THERE'S MORE TO UNDERSTAND ABOUT TIME OF LIFE UNDERSTANDING WHEN CARDIO CARDIOVASCULAR RISK FACTORS ARE MOST IMPORTANT TO CONTROL OR LET A LITTLE BIT ABOVE GOALS OUT THERE IN THE LITERATURE. SO AGAIN THOUGH PRIMARY PREVENTION OF DEMENTIA THROUGH SOCIAL BEHAVIORAL EXPANDED EDUCATIONAL OPPORTUNITIES INCREASE PHYSICAL ACTIVITY APPEARS POSSIBLE AND VALUABLE. WE THINK THE FUTURE TRACKING OF DEMENTIA INCIDENCE AND PREVALENCE IN REPRESENTATIVE POPULATIONS EXTREMELY IMPORTANT GIVEN THE GROWING SIZE OF THE POPULATION. AND THE FUNDING, INCREASE FUNDING FROM NIA STUDIES OF COGNITION DEMENTIA IN THE U.S. AND AROUND THE WORLD WILL FACILITATE TRACKING OF THESE IMPORTANT TRENDS BETTER IDENTIFYING KEY RISK FACTORS AND OUTCOMES. THANKS VERY MUCH. [APPLAUSE] >> TIME FOR A COUPLE OF QUICK QUESTIONS, DR. BENNETT, THEN DR. CUMMINGS. >> VERY NICE, KEN. SO THERE HAVE BEEN TRENDS IN DECREASING STROKE THAT GOES BACK -- THIS MORTALITY FROM STROKE THAT GOES BACK TO 1900, HAVE YOU LOOKED AT TRENDS IN STROKE, I KNOW STROKE OBVIOUSLY CONTRIBUTES TO DEMENTIA, ALSO IMPROVING STROKE SURVIVAL BUT HOW MUCH CHANGE IN THE TRENDS OF ACTUAL STROKE YOU MIGHT HAVE SEEN IN THAT TIME FRAME. >> DEBILE VINE MY COLLEAGUE ON THESE PAPER, A MAIN AREA OF FOCUS, IS FOCUSING IN ON THAT. THAT'S PART OF THE STORY, IT'S INTERESTING, COULD BE TWO EDGE SWORD KEEPING FOLKS WITH STROKE, BUT WOULD HAVE DIED 20, 30 YEARS AGO, MAYBE AT HIGHER RISK FOR DEMENTIA TO TRY TO UNDERSTAND HOW THAT IS PLAYING OUT IS IMPORTANT BUT MAYBE A COUPLE OF YEARS WE CAN HAVE THAT DATA FOR YOU TOO. >> VERY INTERESTING. I THINK THIS MIGHT BE MORE GENERALIZED THAN JUST A DECREASE IN STROKE AND DEMENTIA. WE HAVE SEEN PRETTY PARALLEL 20% DECREASE IN HIP FRACTURE IN OSTEOPOROSIS BY ABOUT HALF, DECREASE IN COLON CANCER, DECREASE IN MI, THE LIST CAN GO ON, IF YOU SUGGEST IT'S MORE THAN JUST CHANGES IN RISK FACTORS FOR EACH OF THESE DISEASES. POSTULATING THAT THERE IS UNDERLYING CHANGE IN AGING. DEGENERATIVE CHANGES THAT COULD INFLUENCE, REALLY IS THE ONLY EXPLANATION FOR INFLUENCE IN ALL THESE AGE RELATED DISEASES AND THE UNITED STATES AND EUROPE AS WELL? >> TIME IS TIGHT HERE. I SEE MORE HANDS GOING UP, DR. KINGTON, DR. MAYO AND ANDERSON. I WILL STOP IT THERE. >> I WAS INTRIGUED BY THE FINDING THAT YOU HAVE OBVIOUSLY SHOWN THE INCREASING RISK FOR AFRICAN AMERICANS BUT ONE CHALLENGE THAT YEAR OF EDUCATION FOR THE COHORT IS VERY DIFFERENT BY RACE. DOLLARS EXPENDITURES, EVERYONE'S SEGREGATED SYSTEMS FOR BIG CHUNKS OF EDUCATIONAL EXPERIENCE, HAVE YOU THOUGHT ABOUT HOW THE LONG TAIL OF JIM CROW, BECAUSE IT'S SORT OF THIS LONG ECONOMIC IMPACT YET ANOTHER IMPACT OF CLEAR EXTREME DIFFERENCES IN QUALITY OF EDUCATION. SO YOU THOUGHT ABOUT HOW YOU LOOK AT THAT? IT'S SO HARD TO DO THIS BECAUSE A YEAR OF EDUCATION, A BLACK PERSON OF THIS GENERATION WAS NOT THE SAME AS YEAR OF EDUCATION FOR A WHITE PERSON. >> AGREE. 100%. I'M CONVINCED THAT THAT'S PART OF THE STORY OF THE RACIAL DIFFERENCE THERE. JIM MANLY, RICHARD'S COLLEAGUES AT COLUMBIA LOOKED AT THIS IN WHITE CAP AND OTHER DATA SETS. AND I THINK BASICALLY FINDING SUPPORT THAT THE IDEA, LOOKED AT AREAS WHERE NUMBER OF SCHOOL DAYS AND TEACHER LEVELS TO GET AT THIS QUALITY QUESTION, IS A HUGE ONE. UNDERSTANDING THAT AND ITS IMPACT ON COGNITIVE RESERVE. I'M CONVINCED THAT'S PART OF THE ISSUE GOING ON HERE. >> IT'S IMPORTANT TO KEEP IN MIND. THERE'S BEEN AT LEAST THREE LARGE AUTOPSY SERIES THAT SHOW THAT PEOPLE WHO WERE CLINICALLY NORMAL DURING LIFE HAD FULL BLOWN PATHOLOGY. AND VASCULAR DISEASE. AND UNTIL WE SHOW THAT'S DECREASING THE JURY IS STILL OUT WHETHER ALZHEIMER'S DISEASE -- IT IS A SYSTEMIC DISEASE. THE VASCULAR RISK FACTORS DON'T RELATE TO THE ALZHEIMER'S PATHOLOGY TO PLAQUES AND TANGLES AT ALL, THERE'S NO CORRELATION, THERE'S TWO STUDIES IN THAT DATABASE TO SHOW THAT, WHAT IT RELATES TO, VASCULAR RISK FACTORS CAUSE VASCULAR DISEASE, IT'S THE CHANGES THAT ARE RELATED TO AMYLOID PLAQUE AND NEUROFIBRILLARY TANGLES SO IT HAS TO GO THROUGH THE BRAIN. BEFORE WE CAN CONSIDER ALL THE VASCULAR -- >> EVEN AS GENERAL INTERNIST I WOULD AGREE THE BRAIN IS VERY IMPORTANT DEMENTIA. BUT WE CERTAINLY DON'T HAVE THOSE DATA IN HRS BECAUSE WE HAVEN'T DONE IMAGING THE ROTTERDAM STUDY DID SHOW DECREASE IN -- BETWEEN 1990 AND 2010 IN BRAIN -- INCREASE IN BRAIN SIZE DECREASE IN VASCULAR LESIONS, ANOTHER STUDY, IN THE NETHERLANDS OR SOMEWHERE THAT FOUND DECREASING AMYLOID IN BRAIN IN THEIR STUDY. THE JURY IS STILL OUT WHAT PATHWAYS ARE, THE COGNITIVE RESERVE ISSUE AND HOW THAT'S PLAYING INTO THESE BRAINS YOU'RE TALKING WITH THE PATHOLOGY BUT FOLKS STILL DOING WELL, TO ME THAT'S THE FASCINATING PIECE HERE. >> THANK YOU, DR. LANGA. [APPLAUSE] >> THE LAST PRESENTATION BEFORE LUNCH BREAK IS BY DR. DAVID HOLTZMAN WHO WILL BE INTRODUCED BY DR. MIKE MAKAWICH, >> IT'S PLEASURE TO INTRODUCE DR. DAVE HOLTZMAN, HE IS ANDREW B. DEADLY WEAPON CHEN P. JONES PROFESSOR AND CHAIR WASHINGTON UNIVERSITY SCHOOL OF MEDICINE, HE'S LONG INTEREST IN PATHOGENESIS ALZHEIMER DISEASE AND OTHER DISEASES, HIS SEMINOLE PAPER ON AMYLOID DYNAMICS AND SLEEP WAKE CYCLE OPEN OUR EYES ON A VERY NEW FIELD AND THAT IS POTENTIAL LINK BETWEEN DISRUPT SLEEP AND CLOCK AND NEURODEGENERATION. DAVE. >> THANKS SO MUCH, IT'S A PLEASURE TO TELL YOU ABOUT AN AREA OF SCIENCE THAT I NEVER THOUGHT WE WOULD END UP STUDYING. BUT JUST BY MAKING SOME ON VARIATIONS BY STUDYING THE METABOLISM OF SOME OF THE PROTEINS INVOLVED IN ALZHEIMER'S DISEASE LED US INTO STUDYING SLEEP. SO I WILL TELL YOU HOW THAT STORY EVOLVED OVER TIME. TO MAKE SURE EVERYONE IS ON THE STATEMENT PAGE, YOU'RE AWARE THAT THE MAIN PATHOLOGICAL FEATURES THE PURE FORM OF ALZHEIMER'S DISEASE WAS ACCUMULATION OF A BETA PEPTIDE AN EXTRA CELLULAR SPACE OF THE BRAIN AMYLOID PLAQUES AS WELL AS ACCUMULATION AND CELL BODIES AN DENDRITES OF HYPERPHOSPHORYLATED AGGRAVATED FORM OF TAU PROTEIN AND A VARIETY OF OTHER CHANGES SUCH AS INCREASES IN THE INNATE IMMUNE RESPONSE AS WELL AS SYNAPTIC LOSS. A CONCEPT THAT'S VERY WELL ACCEPTED THROUGH THE FIELD WHICH PEOPLE HAVE BEEN TALKING ABOUT NOW FOR SOME TIME, IS THAT AT LEAST DISEASE WE KNOW OF AS ALZHEIMER'S DISEASE DOESN'T START WHEN PEOPLE BECOME SYMPTOMATIC, IT PROBABLY BEGINS FROM A PATHOLOGICAL STANDPOINT ROUGHLY WITH THE ACCUMULATION OF THE A BETA PEPTIDE IN THE BRAIN AND AMYLOID PLAQUES WHICH MAYBE OCCURS 15 YEARS OR SO, BEGINS TO OCCUR 15 YEARS OR SO BEFORE SYMPTOMS BEGIN. AT SOME POINT BEFORE THE BEING OF SYMPTOMS, THERE'S THE SPREAD OF HYPERPHOSPHORYLATED FORM OF TAU, THAT'S AGGRAVATED OUTSIDE THE FRONTAL MEDIAL TEMPORAL LOBE AS MUCH AS FIVE YEARS BEFORE ON SEPTEMBER OF ACCEPTANCE. WHEN ONE THINKS ABOUT ANYTHING THAT MODIFIES ANY OF THE PATHOLOGY OF THE DISEASE IN SOME WAY, ONE NEEDS TO ASK WHERE IS IT MODIFYING SOMETHING POTENTIALLY? SO THIS IS A COMPLICATED BUT MODIFIED VERSION OF AMYLOID CASCADE HYPOTHESIS FOR A VARIETY OF FACTORS SUCH AS WHICH WE HAVE JUST BEEN TALKING ABOUT SUCH AS STROKE, DIABETES, ET CETERA, MAYBE SEPARATELY IMPACTING ON THE PROCESS OF CERTAIN AD BUT THERE'S A VARIETY OF FACTORS THAT IS AFFECTING THE PROCESS OF A BETA AGGREGATION IN THE BRAIN AS WELL AS HOW A BETA INFLUENCE IT IS CONVERGENT OR SPREAD OF T A,U TO FORMS THAT ARE DAMAGING THE BRAND. WHAT I WILL FOCUS ON TODAY IS THE IDEA THIS PROCESS MAYBE IMPACT -- MAY THE IMPACT BE MODIFIED SLEEP WAKE CYCLE AND SYNAPTIC ACTIVITY AND THING THAT INFLUENCE NORMAL BRAIN FUNCTION ITSELF. ONE OF THE WAYS WE INITIALLY STARTED TO GET INTERESTED IN THIS TOPIC IS OBSERVATIONS MADE IN HUMANS BY A NUMBER OF GROUPS, NAMELY THAT IF YOU BEGIN TO LOOK AT WHERE AMYLOID DEPOSITION BEGINS IN THE BRAIN OF PEOPLE, GENERALLY APPEARS TO OCCUR WITHIN THIS BRAIN NETWORK, DEFAULT MODE NETWORK FIRST, LATER ON SPREADS IN MULTIPLE AREAS. ONE QUESTION IS WHY IS IT HAPPENING, IN THIS SELECTIVE NETWORK FIRST, THIS IS NET WORK BRAIN THAT IS MOST ACTIVE WHEN NOT PERFORMING A SPECIFIC COGNITIVE TASK. SO ONE OF THE THINGS THAT MY LAB AND OTHERS SHOWED OVER A PERIOD BETWEEN AROUND 2003 TO 2008 IS THAT SYNAPTIC ACTIVITY ITSELF APPEARS TO DRIVE INCREASE OF THE A BETA PEPTIDE IN THE BRAIN UNDER NORMAL CIRCUMSTANCES AND ONE OF THE WAYS THIS HAPPENS IS THAT WHEN SYNAPTIC VESICLES VIEWS SYNAPTIC MEMBRANE THEY'RE RAPIDLY ENDOCYTOSED AND THE AMYLOID PRECURSOR PROTEIN IS ENDOCYTOSED AS BY-PRODUCT OF THIS AND THAT LEADS TO INCREASED FORM OF PEPTIDE. THERE'S INCREASE IN PRODUCTION OF PEPTIDE FROM POST SYNAPTIC ACTIVITY AS WELL. ONE POSSIBILITY IS THE REASON THESE REGIONS OF THE BRAIN ARE MORE VULNERABLE TO GET AMYLOID DEPOSITION IS OVER A LIFETIME REGIONS OF THE BRAIN ARE SYNAPTICALLY ACTIVE. SO IS THERE ACTUALLY EVIDENCE FOR THIS? ONE THING WE FOUND IN STUDYING ANIMAL BRAIN IS IF YOU LOOK AT THE ENDOGENOUS LEVEL OF THE A BETA PEPTIDE DIFFERENT BRAIN REGIONS IN MICE, THE LEVEL OF THE PEPTIDE CORRELATE WITH THE REGIONAL NEURONAL ACTIVITY THAT'S OCCURRING IN THOSE BRAIN REGIONS. AND THEN SUBSEQUENTLY IF YOU FOLLOW AN ANIMAL THAT'S PRONE TO DEVELOP AMYLOID DEPOSITION THOSE REGIONS WITH MORE ACTIVITY GET THE MOST AMYLOID DEPOSITION. IF YOU DO MANIPULATION OF PHYSIOLOGICAL LEVELS OF ACTIVITY, IN THIS CASE WE SIMPLY MANIPULATED THE WHISKER BARREL SYSTEM BY STIMULATING THE WHISKERS ANIMAL, IT GOES UP ACUTELY OVER HOURS, MINUTE, IF YOU CUT THE WHISKERS OVER A MONTH, THERE'S ACTUALLY LESS AMYLOID ACCUMULATION THAT OCCURS IN THAT BRAIN REGION. SO WHEN WE WERE IN THE PROCESS OF STUDYING THESE PHENOMENON, JUST MEASURING, WE DEVELOPED A TECHNIQUE TO MEASURE THE A BETA PEPTIDE IN LIVING ANIMALS OR PEOPLE BY MICRODIALYSIS, THEY HAVE A SMALL PROBE IN BRAIN OF ANIMAL AND YOU CAN MEASURE PEPTIDE HOUR, AND ANOTHER MANIPULATION MEASURED EVERY FEW MINUTES BUT WE'RE MEASURING THE A BETA PEPTIDE IN ANIMALS FOLLOWING OVER TIME AND VARIOUS GRADUATE STUDENT MADE THE OBSERVATION THAT THE A BETA PEPTIDE APPEARED HIGHER DURING THE DARK PHASE AND LOWER DURING THE LIGHT PHASE OF THE DAY. YOU CAN SEE HIGH DURING DARK, LOW DURING LIGHT UP AND DOWN AND OF COURSE RODENTS ARE NOCTURNAL SO THEY'RE AWAKE MORE DURING THE DARK PHASE AND SLEEPING MORE DURING THE LIGHT PHASE. AND IN FACT IF YOU SEE A PRETTY NICE CORRELATION BETWEEN THE MINUTES AWAY AND LEVELS OF A BETA PEPTIDE, ONCE WE STUMBLED ACROSS THE FINDING WE BEGIN SLEEP WAKE CYCLE CAUSING THIS PHENOMENON. AROUND THE SAME TIME ONE OF MY COLLEAGUES AN FORMER TRAINEES RANDY BAITMAN WAS STUDYING LEVELS OF A BETA PEPTIDE IN CEREBRAL SPINAL FLUID OF PEOPLE THAT HAVE LUMBAR CATHETER IN PLACE, HE FOUND IN YOUNGER INDIVIDUALS THAT THE LEVELS OF THE PEPTIDE ALSO ARE HIGHER DURING WAKEFULNESS OR LOWER DURING THE SLEEP, BUT 20% PER DAY THAT WAS OCCURRING. SO JUST TO GIVE THIS FEELING WHAT SOME OF THE THINGS THAT WE THOUGHT MIGHT BE CAUSING THIS, THIS IS ANOTHER STUDY MEASURING THE A BETA PEPTIDE LIGHT PHASE ANIMALS ARE ASLEEP VERSUS DARK PHASE AND YOU CAN SEE THE PEPTIDES IN THE ANIMALS ABOUT 30% HIGHER DURING THE DARK THAN LIGHT. AND WHAT I FOUND VERY INTERESTING IS THAT WHEN WHEN HE MEASURED A SURROGATE OF NEURONAL ACTIVITY WHICH IS LACTATE, LACTATE IS INCREASED WITH NEURONAL ACTIVITY IN VITRO AND IN VIVO, YOU CAN SEE THAT AS SOON AS THE ANIMAL GOES FROM MORE SLEEPING TO MORE AWAKE LACTATE GOES UP 35% AS WELL. THERE SEEMED TO BE A STRONG CORRELATION BETWEEN LEVELS OF PEPTIDE AND IN THIS CASE SURROGATE OF NEURONAL REGIONAL NEURONAL ACTIVITY WITH LACTATE. WE WONDERED BASICALLY IF POSSIBLE WHAT'S GOING ON WITH SLEEP WAKE SOME NEURONAL ACTIVITY IN THE BRAIN REGION IS HIGHER DURING WAKE LOWER DURING SLEEP. TO BEGIN TO FURTHER TEST THIS IDEA ONE THING THAT WE WANTED TO DO IS PROVIDE A STIMULUS TO THE ANIMAL TO INCREASE WAKE OR SLEEP. NOT JUST BEHAVIORAL. SO WHAT WE FIRST DID IS ADMINISTERED A WAKE PROMOTING NEURAL PEPTIDE TO THE ANIMALS WHILE MEASURING THE A BETA PEPTIDE, SO WHAT WOULD HAPPEN IS PEPTIDE WHEN THEY GO INTO THE LIGHT PHASE WE CONTINUE TO GO DOWN, WHEN WE ADMINISTER IN THE BRAIN DIRECTLY IT ACTUALLY KEPT THE PEPTIDE HIGHER DURING THAT ADMINISTRATION. AND THE ANIMALS WERE MORE AWAKE. WE THEN DID THE CONVERSE EXPERIMENT AND GAVE RECEPTOR ANTAGONIST IN THE BRAIN AND YOU CAN SEE THAT NORMALLY A BETA PEPTIDE GOES UP DURING THE DARK PHASE AND THAT INCREASE WAS ATTENUATED BY (INDISCERNIBLE) THESE STUDIES LED US TO WONDER OKAY, THESE ARE THE ACUTE EFFECTS ON THE SOLUBLE FORM OF THE PEPTIDE, WE MAKE IT ALL THE TIME, WHAT WOULD HAPPEN IF YOU CHRONICALLY MODIFY SLEEP AND WAKE, NOT JUST ACUTELY AND WOULD THIS AFFECT PATHOLOGY OR NOT. MIRANDA LAMB, A NEUROLOGY RESIDENT AT THE TIME IS NOW A VERY SUCCESSFUL JUNIOR FACULTY MEMBER AT OREGON HEALTH SCIENCES. DID AN EXPERIMENT WHERE SHE -- WE SLEEP DEPRIVED MICE THAT WERE PRONE AMYLOID DEPOSITION FOR SIX WEEK PERIOD RIGHT AT THE TIME THEY OTHERWISE WOULD BE JUST BEGINNING TO DEVELOP THIS PATHOLOGY. WHAT WE FOUND IS THAT THIS DURING -- IF YOU DID THIS DURING THIS PERIOD THEY INCREASE -- THAT INCREASED AMYLOID DEPOSITION BY TWO AND A HALF FOLD DURING THAT WINDOW OF TIME. IN ORDER TO DO THE CONVERSE EXPERIMENT YOU TOOK THE SAME TYPE OF ANIMALS AND ADMINISTERED RECEPTOR ANTAGONIST TO SLEEP A LITTLE BIT MORE DURING THE SIX WEEK PERIOD, THEN SHE SAW EXACTLY THE OPPOSITE EFFECT WHERE THE ANIMALS GIVEN THE RECEPTOR ANTAGONIST AT LESS AMYLOID DEPOSITION. SO THE MECHANISM THAT I WAS TRYING -- THAT WE WERE TRYING TO FURTHER UNDERSTAND AT THE TIME WAS THAT PERHAPS THE REASON THAT SLEEP WAKE IS ALTERING AT LEAST THIS PEPTIDE AND THE RISK WERE GETTING PATHOLOGY WAS DUE TO THE FACT THAT DURING WAKE YOU GENERALLY HAVE NEURONAL ACTIVITY THAN DURING SLEEP. ANOTHER HYPOTHESIS IS EMERGED OVER THE LAST FEW YEARS WHICH HAS COME FROM MACON NEDERGARD LAB, CLEARANCE OF PEPTIDE OVER BRAIN WAKEFULNESS CLEARANCE OF THE PEPTIDE IS CLEARED SO WHAT WE STILL DON'T COMPLETELY UNDERSTAND WHICH OF THESE TWO MECHANISMS OR WHETHER BOTH IS LEADING TO THIS PHENOMENON. THIS IS AN AREA RIPE FOR FUTURE STUDY IN TERMS OF DEVELOPING WAYS TO POTENTIALLY PREVENT THIS PHENOMENON. SO ONE OF THE THINGS THAT WE ALSO BECAME INTERESTED IN IS A FOLLOW-UP TO THIS WAS OKAY, WELL, REPIN PROMOTES WAKEFULNESS AND WE ACTUALLY SHOW BY PHARMACOLOGICAL MEANS THAT ARCREXIN NOT BEHAVIORAL BY THROUGH IT AFFECTS SLEEP, AND A BETA AND THERE'S WAYS TO DO THIS BY USING GENETICALLY MODIFIED ANIMALS. SO A NUMBER OF YEARS AGO AREXIN KNOCKOUT MICE CREATED WITH FEATURES OF NARCOLEPSY, THE INABILITY TO MAINTAIN WAKEFULNESS, INTERESTINGLY THE ANIMALS HAVE TEN PERCENT GREATER SLEEP OVER ALL. WE DID A SIMPLE EXPERIMENT CROSSING MICE WITH AMYLOID DEPOSITION WITH AREXIN KNOCKOUT MICE AND THE RESULT WAS OBVIOUS THAT THE ANIMAL THAT LACKED AREXIN HAD LESS AMYLOID DEPOSITION. GIVEN THIS WE WANT TO KNOW IF AFFECT OF AREXIN AFFECTING LOCAL ARCREXIN SIGNALING THROUGHOUT DIFFERENT BRAIN REGIONS OR IS IT THROUGH AREXIN AFFECTING THE SLEEP WAKE CYCLE IN GENERAL. SO IN ONE EXPERIMENT, GENE AVENUE A POST-DOCTORAL FELLOW ADMINISTERED AREXIN SPECIFICALLY INTO THE HIPPOCAMPUS AN FOLLOWED THE MYSELF FROM THREE TO SIX TO NINE MONTHS, WE JUST ADMINISTERED ARCREXIN IF THE IN THE BRAIN IT DIDN'T AFFECT AMYLOID DEPOSITION AT ALL, IN CONTRAST WE WANTED TO ASK YOU TAKE THESE MICE THAT LACK AREXIN AND PUT THEM IN THE BRAIN BUT ONLY IN THE SMALL REGIONS OF THE HYPERTHALAMUS THAT EXPRESSES ARCREXIN, WILL THAT RESTORE THE PATHOLOGY THAT WE WERE SEEING BEFORE. SO THIS IS A DIAGRAM OF THIS SMALL REGION OF HYPOTHALAMUS THAT EXPRESSES ARCREXIN IN NORMAL MOUSE, THIS IS A KNOCK OUT WITH NO EVIDENCE OF AREXIN AND WE BASICALLY USING VIRAL VECTORS REPLACED -- PUT IT BACK INTO ADULT MICE AT A YOUNG AGE, AND THEN ASKED WHAT HAPPENS TO AMYLOID DEPOSITION WHEN YOU DO THIS. AND WHAT YOU CAN SEE IS LITTLE HARD TO SEE WITH THE IMAGE BUT BY PUTTING AREXIN BACK INTO THE SELECT REGION OF THE BRAIN THAT CAUSED THE AMYLOID DEPOSITION TO COME BACK TO LEVELS THAT WOULD HAVE BEEN OTHERWISE. SO WHILE WE HAVE EVIDENCE THAT BEHAVIORAL PHARMACOLOGICAL GENETICALLY MANIPULATING SLEEP, THAT INFLUENCES THE A BETA PEPTIDE ACUTELY AND CHRONICALLY. BUT THESE MANIPULATIONS HAVE COMPOUNDS THAT CAN AFFECT STRESS, ET CETERA SO ONE OF THE THINGS THAT WE'RE WORKING ON NOW IS TO ASK THE QUESTION ARE THERE OTHER WAYS TO AFFECT SLEEP, AND SEE WHETHER IT'S THE SLEEP WAKE CYCLE SPECIFICALLY CAUSING THIS VECTOR SPECIFIC REGIONS OF THE BRAIN WITH DREADS AND OPTOGENETICS SO DREADS IS A DESIGNER RECEPTOR ACTIVATED BY DESIGNER DRUGS. SO THESE ARE BASICALLY G PROTEIN COUPLED RECEPTORS, THEY'RE ENGINEERS WHERE YOU PUT THEM INTO A CELL AND NOT ACTIVATED IN THIS CASE, MUTANT CHOLINE RECEPTORS, THEY DON'T RESPOND TO ACETYL CHOLINE BUT ACTIVATED BY A DESIGNER DRUG, WHICH IS NOT OTHERWISE ACTIVE. THE DIAGRAM WHAT THIS LOOKS LIKE FORWARD. ONE NICE THING USING THESE IS THAT YOU CAN GET A WAY WITH NOT HAVING SOME OF THE UNDESIRED AFFECTS OR OFF TARGET ACTS BY SPECIFICALLY PUTTING RECEPTORS IN PARTICULAR PARTS OF THE BRAIN. I WON'T SPEND TIME ON THIS BUT THE RECEPTOR THAT WE HAVE BEEN USING IN COLLABORATION WITH -- GROUP USING THIS TECHNOLOGY FROM -- IS TO USE THIS M 3-DQ RECEPTOR WHICH WHEN IT'S TURNED ON WITH CNO THIS DRUG WILL TURN ON NEURONAL ACTIVITY IN THE CELLS IT'S EXPRESSING. THERE ARE SOME ADVANTAGES, THE OTHER WAY ONE CAN MODIFY NEURONAL ACTIVITY ACUTELY IS WITH THE PUBLICIZED AND INTERESTING TECHNIQUE OPTOGENETICS. ONE ADVANTAGE IS IT TENDS TO MORE PHYSIOLOGICALLY ACTIVATE ACTIVITY, IT DOESN'T TURN IT ON IMMEDIATELY, IT'S ON SLOWER, IN ADDITION YOU CAN ALSO ADMINISTER CNO AND AFFECT ACTIVITY OVER LONG -- MUCH LONGER PERIODS OF TIME IN A MORE FACILE WAY. SO THE WAY THIS WORKS IS THAT TYPICALLY ONE USES A VIRAL VECTOR IN A VERY SMALL REGION OF THE BRAIN YOU CAN EXPRESS THESE DREADS AND THE CONSTRUCTS THAT HAVE BEEN MADE ARE INVERTED SO WHEN YOU PUT THEM IN, THE CHANNELS ARE NOT TURNED ON. PLAGUED BY THESE LOX P SITES SO IF YOU PUT INTO AN ANIMAL THAT EXPRESSES CREE RECOMBINATION WHEREVER YOU PUT THE CONSTRUCT ONLY IN THAT REGION WILL THE CRE RECOMBINASE EXPRESSED THERE FLIP THE CONSTRUCTS SO THAT THE CHANNEL IS EXPRESSED. THERE'S PRELIMINARY DATA THIS IS SOMETHING WE'RE ACTIVELY ENGAGED IN. SO THERE'S TWO REGIONS OF THE BRAIN KNOWN TO PROMOTE -- THERE'S MORE BUT TWO THAT ARE KNOWN TO POTENTIALLY MANIPULATE ALREADY TO PROMOTE WAKEFULNESS, ONE PART OF THE BAY ZILLION FOREBRAIN. AND CLIFF AND COLLABORATORS HAVE FOUND IF YOU TURN ON NEURONAL ACTIVITY IN THE SUPER MAMILLARY LIEU NUCLEUS TURN ON WAKEFULNESS FROM THE MOMENT YOU STIMULATE THAT REGION. WE CAN COLLABORATE AND NOW TAKEN THIS TECHNOLOGY, A TALENTED POST-DOC WERE GOING THESE EXPERIMENTS WHERE ESSENTIALLY USING VIRAL VECTORS PUT THESE CONSTRUCTS INTO THE BRAIN 30 DAY BEFORE THE EXPERIMENT AND THEN YOU CAN PUT ON ELECTRODES TO MONITOR SLEEP AND THE ANIMALS HABITUATE TO THIS CONDITION AND BASICALLY YOU MONITOR SLEEP WAKE CYCLE AND ADMINISTER CNO TO TURN ON CHANNELS AT A PARTICULAR TIME AND MEASURE WHAT HAPPENS TO THE ANIMAL. SO THIS GIVES YOU ONE EXAMPLE IS MEASURENING A MOUSE AMOUNT OF RIM SLEEP EVERY HOUR FOR 24 HOUR PERIOD IN ANIMALS WE GAVE THE CNO TO WHICH THE SUPERMAMILLARY NUCLEUS WAS TARGETED THERE'S NO EFFECT ON RIM SLEEP, WHAT'S INTERESTING IS WE GAVE CNO, IT LOOKS LIKE HERE AT 6 IN THE MORNING, IMMEDIATELY UPON GIVING THE CNO, GOES FROM HAVING WAKEFULNESS 40% OF THE TIME TO 100% OF THE TIME. THIS LASTS ONE INJECTION FOR SIX TO EIGHT HOURS. NORMALLY A MOUSE WHEN MORE AWAKE DURING THE DARK PHASE WOULD BE AWAKE ABOUT 70, 75% OF THE TIME, THIS IS A HUGE EFFECT, IT'S JUST VIRTUALLY COMPLETE WAKEFULNESS WHICH IS NEVER SEEN NORMALLY IN A MOUSE. AND THIS COMES BACK TO NORMAL. WHAT'S ALSO VERY INTERESTING IS WHEN YOU SLEEP DEPRIVE AN ANIMAL OR A HUMAN, THERE'S A PHENOMENON CALLED SLEEP REBOUND WHERE YOU REALLY SLEEP MORE WHEN YOU DO MANIPULATIONS LIKE THIS, WHEN YOU MANIPULATE THE NUCLEUS, THERE'S NO REBOUND. THEY'RE AWAKE AND BACK TO NORMAL. REALLY FASCINATING. AND THEN OF COURSE IF THERE ARE MORE AWAKE THEN THEY'RE NON-REM SLEEP. VERY ABNORMAL AND THEN THEY RETURN TO NORMAL. WHEN THE PROCESS TRYING TO STUDY THE EFFECT OF THIS ON SOME OF THE PARAMETERS I WAS SHOWING EARLIER SUCH AS LEVEL OF AMYLOID PEPTIDE, CHRONIC EFFECTS, ET CETERA, HOPEFULLY BE ABLE TO FIND THAT OUT OVER THE NEXT YEAR. SO ONE OF THE THINGS THAT WE'RE ALSO VERY INTERESTED IN IS ONCE THE PROTEINS LIKE A BETA OR TAU OR OTHER THINGS BUILD UP IN THE BRAIN, IS THAT ASSOCIATED WITH CAUSING ABNORMALITIES IN THE SLEEP WAKE CYCLE THAT WE KNOW OCCUR IN HUMANS, BUT ALSO OCCUR IN ANIMALS, IS PROTEIN AGGREGATION RESPONSIBLE FOR THE ABNORMALITIES IN THE SLEEP WAKE CYCLE. SO ONE OF THE STUDIES WE PUBLISHED A FEW YEARS AGO IF YOU FOLLOW AMYLOID DEPOSITION IN DIFFERENT MICE, THAT ARE ENGINEERED TO DEVELOP THIS, YOU CAN SEE THIS NORMALLY. SOME OF THESE PSA MICE NINE MONTHS THERE'S A FAIR AMOUNT OF AMYLOID DEPOSITION, WE FOLLOW THE SLEEP WAKE CYCLE IN THESE MICE AND WHAT YOU CAN SEE IS IF YOU FOCUS ON THIS MIDDLE PANEL, BY NINE MONTHS OF AGE THEY ACCUMULATE AMYLOID, THEY ARE AWAKE ABOUT 50% MORE THAN NORMAL AS THEY ACCUMULATE AMYLOID IN THE BRAIN. SO ONE OF THE QUESTIONS IS THAT LEADS TO AGING OR DO ACTUAL AMYLOID ACCUMULATION OR DUE TO SOME OTHER TRANSGENE EFFECT SO IN ORDER TO ADDRESS THIS WE STARTED VACCINATING THE MICE WITH THE AMYLOID PEPTIDE WHICH AS YOU KNOW ARE SOME OF THE KINDS OF TREATMENTS THAT ARE IN CLINICAL TRIALS RIGHT NOW IN HUMANS. WHEN YOU DO THIS VAX MAKES EARLY IN LIFE THE ANIMALS THAT DEVELOP A LOT OF AM LOUT DEPOSITION BASICALLY ARE PREVENTED FROM GETTING AMYLOID DEPOSITION. AND WHEN WE DO THAT, WE ALSO ASSESS WHETHER THIS AFFECTS THE SLEEP WAKE CYCLE SO THE ANIMALS NOT VACCINATED THEY WERE AWAKE ABOUT MUCH MORE THAN NORMAL. COMPARED TO NORMAL MOUSE, ABOUT 50% MORE THAN NORMAL. IN THE VACCINATED MICE, THIS POOR SLEEP WAS COMPLETELY ATTENUATED BY THE VACCINATION. SO THAT ARGUES ACCUMULATION OF A BETA PEPTIDE IN THIS MODEL NOT OVEREXPRESSION OF THE PRECURSOR PROTEIN THAT'S CAUSING THE SLEEP WAKE ABNORMALITY. SO WHAT'S THE EVIDENCE THAT THIS MIGHT BE REALLY IMPORTANT IN HUMANS OR NOT. ONE STUDY THAT ONE FOLLOW DID A FEW YEARS AGO IS TO LOOK AT PATIENTS THAT CAME THROUGH OUR ALZHEIMERS DISEASE RESEARCH CENTER INVOLVED IN DIFFERENT STUDIES THAT WERE COGNITIVELY NORMAL. SOME OF WHOM HAD AMYLOID DEPOSITION AND SOME WHOM DID NOT. WHAT YOU CAN -- WHAT SHE FOUND IS SLEEP QUALITY WAS SIGNIFICANTLY WORSE IN PEOPLE WITH AMYLOID DEPOSITION EVEN BEFORE COGNITIVELY IMPAIRED. AND IN A RECENT STUDY BY MATT WALKERS GROUP AT BERKELEY THEY FOUND SOMETHING SIMILAR, AMYLOID POSITIVE OR NEGATIVE AND DIRECTLY STUDIED SLEEP AND FOUND THAT NON-RIM SLEEP WAS DISRUPTED IN THOSE WITH AMYLOID DEPOSITION. THIS WAS LINKED TO POOR MEMORY. THIS IS AN AREA THAT NEEDS MORE STUDY BUT IT'S VERY INTERESTING IN RELATION TO THE ANIMALS. SO THE FINAL THINGS I WANT TO TOUCH ON IS THAT ONE OF THE OTHER MAJOR PATHOLOGIES OF ALZHEIMER'S DISEASE OF COURSE IS THE ACCUMULATION OF NEUROFIBRILLARY TANGLE PATHOLOGY, IN FACT THE ACCUMULATION OF TAU IS MUCH BETTER COATERLATED WITH THE DAMAGE -- CORRELATED WITH THE DAMAGE IN THE BRAIN ATROPHY OR CLINICAL DECLINE. SO WE JUST STARTED TO ASK THE QUESTION IS ACCUMULATION OF TAU IN ANIMAL MODEL LINKED WITH SLEEP ABNORMALITIES. AS YOU ARE AWARE, THE AAU ON THINKS DON'T INCLUDE ALZHEIMER'S DISEASE, THERE'S PRIMARY TAU ON THINKS AND MANY INDIVIDUALS WHEN THEY BECOME IMPAIRED HAVE SLEEP PROBLEMS. IN FACT, MORE SO EVEN IN PATIENTS WITH ALZHEIMER'S DISEASE. SO GERALD HOLDIS HAS BEGUN TO EXAMINE SLEEP ABNORMALITIES IN MICE WITH TAU ON THINK. ONE MODEL WE STARTED TO USE IN TAUOPATHY, THIS MODEL WAS FIRST DEVELOPED BY VIRGINIA LEE'S LAB. THERE'S A NUMBER OF THESE TYPES OF MODELS AROUND. THEY LOOK NORMAL AT A YOUNG AGE OF THREE MONTHS BUT BY SIX MONTHS AND THEN NINE MONTHS THEY BUILT TAU ABNORMALLY TAU AGGREGATION AS WELL AS IMPORTANTLY GET OVER NINE MONTHS OF AGE DEVELOP TRUE NEURODEGENERATION WITH BRAIN ATROPHY AS WELL AS BEHAVIORAL ABNORMALITIES. BRIEFLY WHAT WE ENDED UP FINDING IS THAT IF YOU EXAMINE THESE ANIMALS AT SIX NINE AND 11 MONTHS BY DOING SLEEP STUDIES IS THAT THE FIRST THING WE FIND WRONG AT NINE MONTHS IS DECREASE IN RIM SLEEP, THAT'S VERY INTERESTING BECAUSE THAT'S NOT WHAT WE FOUND IN THE AMYLOID MICE BUT THIS IS WHAT'S OFTEN FOUND IN PATIENTS WHO HAVE TAU OPATHIES, THEY START HAVING RIM PROBLEMS AND LOOKS LIKE LOOKING AT THE BRAIN STEM THIS IS PROBABLY DUE TO TAU ABNORMALITIES OCCURRING IN RIN GENERATING REGIONS. AS THE MICE GET OLDER, WE ALSO FIND THEY HAVE DECREASED SLEEP AS WELL AS INCREASED WAKEFULNESS. WE ALSO CAN LOOK QUANTITATIVELY AT EG POWER AND FIND AS THESE MICE GET OUT TO 11 MONTHS OF AGE THERE'S A STRONG DECREASE IN DELTA POWER IN NON-RIM SLEEP THAT REFLECT IT IS FACT THAT THESE MICE ARE GETTING TRUE NEUROGENERATION IN THE CORTEX. THIS IS A NICE MODEL, QUANTITATIVE MODEL WHERE ONE CAN ASSESS THE EFFECTS OF SLEEP QUANTITATIVELY AND LOOK POTENTIALLY AT WAYS IF YOU DID DEVELOP A TREATMENT FOR SOMETHING LIKE A TAUOPATHY, MAYBE THIS IS A NICE WAY TO MONITOR WHAT YOU'RE HAVING EFFECT NOT ONLY IN ANIMAL BUT TRYING TO SEE WHETHER QUANTITATIVE ASSESSMENT OF SLEEP IN HUMANS MIGHT BE ANOTHER BIOMARKER THAT WOULD BE USEFUL TO ASSESS. SO I THINK WHAT WE FOUND SO FAR IS THAT FRAGMENTED OR ABNORMAL SLEEP CAN DRIVE A BETA RELEASE THAT PROBABLY CAN DRIVE AMYLOID DEPOSITION AND ONCE THIS OCCURS THAT COULD CAUSE FURTHER ABNORMALITIES IN SLEEP AND CREATE A VICIOUS CYCLE. WE'RE TRYING TO NOW SEE WHERE TAU FITS INTO THIS AND WHETHER IT MAY HAVE SIMILAR OR DIFFERENT BEHAVIORS IN REGARD TO THE A BETA PEPTIDE. WHAT I TRIED TO SHOW YOU IS ENDOGENOUS NEURONAL ACTIVITY APPEARS TO REGULATE INTERSTITIAL FLUID LEVELS IN THE BRAIN AND DETERMINE LIKELIHOOD THIS PROTEIN AGGREGATES. THE IMPLICATIONS OF THIS ARE THAT NOT ONLY THE SLEEP WAKE CYCLE BUT OTHER THINGS THAT AFFECT ENDOGENOUS NORMAL ACTIVITY CAN IMPACT ON THE ARTICLE ABILITY OR LIKELIHOOD THAT ONE DEVELOPS THIS PATHOLOGY IN THE BRAIN. BOTH A BETA AND TAU AGGREGATION LEADS TO SLEEP DISRUPTION, THIS MAY OCCUR DURING THE STAGE OF PRE-CLINICAL AD AND THIS IS SOMETHING THAT I THINK NEEDS TO BE STUDIED A LOT MORE IN HUMANS. THERE'S A SERIES OF QUESTIONS I RAISED IN THE NEXT SLIDE BECAUSE OF TIME I WON'T GO THROUGH THEM ALL AND I WILL JUST STOP HERE AND THANK THE PEOPLE IN MY LAB AND OTHERS THAT HAVE CONTRIBUTED TO THESE STUDIES. AND LEAVE TIME FOR QUESTIONS. THANKS. [APPLAUSE] BURNING QUESTION OR TWO OTHERWISE WE'LL TAKE THEM DURING LUNCH. >> DAVID, CONSIDERABLE NUMBER OF PATIENTS WITH ALZHEIMER'S DISEASE HAVE LOUIS BODY PATHOLOGY AND THEY HAVE RIM SLEEP DISORDER. ARE THEY WORSE? ANY MORE AMYLOID DEPOSITION OR HAVE YOU LOOKED AT THAT? >> GREAT POINT. AS YOU KNOW SOME DISORDERS PRESENT WITH A SLEEP PRO MOW YEARS BEFORE SYMPTOMATIC. SO IT I'M IN THE AWARE THAT'S LOOKED AT IN REGARDS TO -- CERTAINLY PATIENTS WITH LEWY BODY DEMENTIA WITH AMYLOID DEPOSITION # 0 TO 80% BUT HOW THOSE ARE INTERACTING TO AFFECT SLEEP AND INTERACT WITH EACH OTHER IS NOT KNOWN. SOMETHING SOME DAY HOPEFULLY WE CAN START TO LOOK AT. >> VERY INTERESTING. OBVIOUSLY THERE'S A PARADOX NEURONAL ACTIVITY IS BAD BECAUSE WE OBVIOUSLY ASSOCIATE LEARNING AND EDUCATION WITH A POSITIVE OUTCOME AND PREVENTION BUT I REALIZE THAT'S OVERSIMPLIFYING THE QUESTION BUT STILL INTERESTING. SO YOU HAD AN INTERESTING WAY OF MODULATING IS THE SLEEP PATTERNS VERY CAREFULLY BUT REALLY THE QUESTION IS, CAN YOU DISSOCIATE SLEEP DISRUPTION FROM NEURONAL ACTIVITY? BECAUSE IF YOU COULD KEEP ANIMALS AT NORMAL SLEEP CYCLE BUT ALTER THE NORMAL ACTIVITY THAT IS POTENTIALLY PATHOGENETIC THAT MIGHT GIVE A CLUE WHETHER IT'S NEURONAL ACTIVITY OPPOSED TO THER THINGS THAT HAPPEN WHILE YOU OFFER SLEEP ACTIVITY. >> GREAT POINT. THERE IS A STUDY THAT MADE POPULAR PRESS IN THE LAST MONTH OR TWO SPECIFICALLY MANIPULATED PATTERNS IN THE BRAIN TO GET BASICALLY SHOW YOU CAN DRIVE LESS ACTIVITY WITH HAVING A 30-HERTZ STIMULATION OF FREQUENCY, THAT WAS DONE IN CONTEXT KEEP SLEEP THE SAME OR ALTERED, THAT WOULD BE INTERESTING TO SEE IF YOU CAN DISSOCIATE THE TWO OR NOT. >> DR. CUMMINS, LAST QUESTION. >> DO YOU STUDY EFFECT TO WHAT OLDER PEOPLE DO TO GET SLEEP, BENZODIAZEPINES ON ACCUMULATION OF BETA TAU? >> NOT EXACTLY BUT ONE THING WE ARE DOING IS LOOKING AT IN HUMANS, WHETHER IF YOU GIVE SOMETHING THAT PROMOTES SLEEP, ACUTELY AND THEN MEASURE THE PEPTIDE IN THE CEREBROSPINAL FLUID IN THE 24 HOUR STUDY, WHETHER THAT MANIPULATES A BETA LEVELS AND YOU ALREADY CAN SEE IF YOU GIVE BENZODIAZEPINE ACUTELY TO CAUSE SLEEP, A BETA LEVELS GO DOWN. WHETHER IT'S CHRONIC EFFECT IS A DIFFERENT ISSUE. >> THANK YOU VERY MUCH, DR. HOLTZMAN. [APPLAUSE] >> WE'LL TAKE A TEN MINUTE BREAK TO GET LUNCH, IF YOU ORDERED LUNCH THEY'RE IN THE NEXT ROOM NOW. WE'LL BE BACK IN TEN MINUTES. >> TO THOSE ON COUNCIL, THE INTRAMURAL LABS GET REVIEWED ONCE EVERY FOUR YEARS BY THE BOARD OF SCIENTIFIC COUNSELORS WHICH IS A GROUP OF EXPERTS WHO WILL GIVE INPUT AS TO THE PROGRESS WITH THAT LABORATORY AND MAKE RECOMMENDATIONS FOR HOW THEY MIGHT GO FORWARD IN THE FUTURE. AND THE JOB OF COUNCIL IS TO REVIEW ALL OF THESE SORTS OF ACTIVITIES. SO THE FIRST PART WILL BE HIGHLIGHTING THE RESEARCH IN COUPLE OF LABORATORIES THEN A CLOSED SESSION WITH JUST COUNCIL AND DR. FERRUCCI IS SCIENTIFIC DIRECTOR TALKING FIRST SPECIFICALLY ABOUT THE RECOMMENDATIONS AND THE ACTIONS TAKEN AS A RESULT OF THOSE RECOMMENDATIONS. SO I SEE DR. SPENCER AND DR. LAKATTA SWITCHING. WHO WILL SPEAK FIRST DR. SPENCER OR LAKATTA? >> DR. SPENCER WHO HAPPENED TO BE HERE BY CHANCE. >> DR. SPENCER WILL BE GIVING YOU AN OVERVIEW OF HIS RESEARCH THE LAST FOUR YEARS. >> THANK YOU VERY MUCH. LET ME PUT A TIMERRER ON THIS TO MY BRAIN, RICHARD SPENTSOR MAKES -- I'M HERE PRESENTING ON BEHALF OF DR. JOSEPHINE EAGAN, LAB CHIEF UNFORTUNATELY ON TRAVEL, LCI INFIELD RESEARCH PROGRAM AT THE NICA HAD SEVERAL SECTIONS, THERE'S MY SECTION, GOES LIKE THIS, THERE'S A NEW SECTION RUN BY CHALLENGING CLINICAL INVESTIGATOR CHRISTOPHER RAMTON AND THE DIABETES SECTION BY DR. EAGAN, ALSO TALKING RESEARCH IN EFFORT BIOCHEMISTRY AND DRUG DISCOVERY UNIT WHICH HEADED BY ERIN WINER BEFORE HE LEFT FOR A DIFFERENT POSITION TAKING CARE OF THIS -- THERE WAS A COUPLE OF SENIOR PEOPLE IN LCI WHO ARE PART OF MY LAB AND RESPECTIVELY. SO I WILL TALK MORE ABOUT MY SECTION FIRST. OVERALL GOAL IS TO PERFORM NON-INVASIVE HISTOLOGY BIOCHEMISTRY USING MRI. I THOUGHT ABOUT THIS, PEOPLE SOMETIMES ASK YOU WHAT YOU DO FOR A LIVING AND WE DIDN'T MAKE PICTURES, WE DON'T REALLY DO SPECTROSCOPY BUT NOT HIRES SO WHAT DO WE DO? HISTOLOGY BIOCHEMISTRY, IN OTHER WORDS, WE TAKE A SAMPLE, CHOP IT UP AND SEE WHAT'S IN IT. MAJOR HISTOLOGIC PREPARATIONS AND ONE OF THE GOALS IN THE GENERAL FIELD OF MRI IS NOT TO MAKE BEAUTIFUL PICTURES, I WILL SHOW YOU SOME TYPE ARE LESS BEAUTIFUL THAN WHAT YOU CAN GET OFF THE STANDARD CLINICAL IMAGER BUT THEY HAVE INFORMATION CONTENT BECAUSE WE OTHER TRYING TO RECAPITULATE THE CAPABILITIES OF MORE PRECISE ANALYTIC TECHNIQUES, OUR THREE MAIN ALLOCATIONS IN MY LAB ARE MYELINATION PATTERNS COGNITIVE IMPAIRMENT AND ALZHEIMER'S DISEASE, THIS IS A NEW THRUST THAT WE HAVE BEEN PUTTING A LOT OF EFFORT INTO, SOMEBODY WE HAVE BEEN STUDYING QUITE A BIT THE LAST SEVERAL YEARS AND IS STILL OF IMPORTANCE TO US IS LOSS AND OSTEOARTHRITIS, AND MORE RECENTLY CHANGING MACRO MOLECULAR CONTENT AND DISORDERS AND FUNCTION IN PARTICULAR SARCOPENIA. WE DO MR FOR A LIVING, HISTOLOGY, WHAT DOES THAT MEAN, THE WAY I FIGURED OUT TO ANSWER THIS QUESTION, IS TO DISSECT THE MR SIGNAL, IN OTHER WORDS YOU HAVE TOTAL MR SIGNAL DRAWN AS EIGHT UNITS ARBITRARY AND IT'S A TOTAL SIGNAL, YOU GET SIGNAL, YOU MANIPULATE THAT IN MANY WAYS FUNCTIONAL IMAGES AND YOU SEE THOSE, IT'S WONDERFUL STUFF. UNDERLYING THAT SIGNAL ARE DIFFERENT WATER MOLECULES TYPICALLY WATER NOT NECESSARILY WATER BUT TYPICALLY WATER, THAT IS MADE UP OF THREE UNITS OF BRAIN OR FIVE UNITS OF WATER IN THE BRAIN. OR YOU CAN BE ONE UNIT OF BRAIN AND SEVEN UNITS OF WATER. THEY MAKE THE TOTAL SIGNAL OF EIGHT SO THIS IS A VERY DIFFICULT PROBLEM TO SOLVE DISSECTING THE SIGNAL INTO ITS COMPONENT PARTS. ANSWERING THAT QUESTION, THOUGH, WHICH IS A TOUGH QUESTION, LET'S DETECT DIFFERENT MACRO MOLECULES IN THE ORGAN OF INTEREST, THIS IS MATHEMATICALLY IN MY LAB, I WON'T SHOW ANY HERE BIT'S PART OF THE MATHEMATICAL AREA KNOWN AS INVERSE PROBLEMS WHERE YOU INFER CAUSES FROM OBSERVING EFFECTS, THIS SOUNDS FOREIGN BUT IT'S JUST SHERLOCK HOLMES DOES YOU READ THE STORY WHICH I HAVE DONE MORE RECENTLY THAN I WOULD LIKE TO ADMIT AND BASICALLY HE OBSERVED THIS AND OBSERVES THIS AND WALKING WITH HIS COME PA DREY WATSON AND SAID SOMETHING ABOUT THIS IS WHAT HAPPENED, THIS IS WHEN THE TRAIN ARRIVED AND EGAD HOW DID YOU KNOW THAT, INFERRED FROM WHAT HE SAW OBSERVATIONS THAT'S AN INVERSE PROBLEM. SO THE FIRST APPLICATION I WILL TALK ABOUT ARE MYELINATION PATTERNS IN COGNITIVE DISEASE, INCREDIBLY POINTER, THERE'S A WELL RECOGNIZED NEED FOR IMAGING BIOMARKERS OF COGNITIVE DECLINE, MYELINATION IS AN EMERGING TARGET AND IT MAYBE VERY KEY BUT IT'S EXTREMELY HARD TO MAP QUANTITATIVELY, THIS IS MAPPED QUALITATIVELY WITH MRI FOR 20 YEARS BUT THE QUALITATIVE MEASURES MEAN OKAY WE USE SOME SORT OF SIGNAL COMPONENT OF T-2, SOMETHING VERY COMMON TRANSFER, WORDS YOU'RE FAMILIAR WITH, THAT REFLECTS MYELIN LOSS, IT REFLECTS IT. IT DOESN'T REALLY QUANTIFY IT SO THE DEGREE OF CHANGE IN THESE PARAMETERS, SAY T-2 FOR EXAMPLE WHATEVER THAT MEANS TO YOU, IT'S A RELAXATION TIME, IT'S SENSITIVE TO MYELIN. BUT IF IT CHANGES BY FACTOR OF TWO, THAT DOESN'T MEAN THE MYLEN CHANGED BUT IS ACCURATE TO, IT'S MARKER, IT'S A HISTOLOGIC STAIN BUT IT'S NOT QUANTITATIVE. SO WE HAVE BEEN WORKING ON TRYING TO MAKE QUANTITATIVE ASSESSMENT OF MYLEN PATTERNS NON-INVASIVELY, THIS REQUIRES PHYSICS AND STATISTICAL METHODS TO IMPROVE UPON THE CURRENT STATE-OF-THE-ART. AND AGAIN, THIS IS ANOTHER WAY OF LOOKING AT THE TEST TUBE OR GRADUATED CYLINDER SHOWN PREVIOUSLY, THIS IS THE TOTAL MR SIGNAL FOR TECHNICAL REASONS IT DECAYS, THIS IS T-2 DECAY IN THIS CASE. THIS IS MEANT TO BE -- MEANT TO BE A SURGEON'S HAND WITH A SCALPEL, THE IDEA HERE WAS SOMETHING ABOUT DISSECTION, SO TRY TO DISSECT THE SIGNAL INTO COMPONENT PARTS, THE MYELIN PART OF THE SIGNAL AND NON-MYELIN PART OF SIGNAL, THIS IS IS A VERY DIFFICULT PROBLEM. OUR APPROACH HAS BEEN BAYESIAN ANALYSIS WHICH I WON'T GET INTO DETAILS, I WILL MENTION -- I WILL SHOW A COUPLE OF EXAMPLES HOW EFFECTIVE THIS IS. THIS IS REFERENCE DATA WE CREATED HIGH SIGNAL TO NOISE. THIS IS A CONVENTIONAL STATE-OF-THE-ART, THIS IS AS GOOD AS IT GETS. IT'S QUITE NICE, YOU CAN SEE PATTERNS OF WHITE MATTER AND GRAY MATTER, SO THAT'S ALL GOOD PUBLISHED STUFF FROM THE RECENT LITERATURE. RESOLUTION ISN'T THAT HIGH BUT WHILE THIS IMAGE IS BEAUTIFUL, IT SHOWS SOMETHING THAT'S DIFFERENT FROM A STANDARD BRAIN IMAGE. A BRAIN IMAGE YOU GET ON STANDARD M SYSTEM IS MA CHU TECHNOLOGY, IT DOESN'T SHOW MYELIN, IT SHOWS STUFF. THIS IS A BAYESIAN METHOD MUCH MORE STABLE, HIGH RESOLUTION IMAGE, I WANT TO MOVE ON NOW TO MORE RECENT RESULTS FURTHER IMPROVING SIGNAL TO NOISE AND BEGINNING TO COLLECT NICE DATABASE MAKING USE OF THE POPULATION AVAILABLE FROM THE NATIONAL INSTITUTE ON AGING IN BALTIMORE WHICH IS ACTUALLY IDEALLY SET UP FOR THIS KIND OF STUDY. SO THIS IS SHOWING SIX SUBJECTS, TWO IMAGING SLICES, LET'S LOOK AT THE YOUNG IMAGE FIRST, SUBJECT 1 AND 2, THESE ARE YOUNG LOOKING BRAINS, FIRST MENTION THE MYLEN, LIGHT COLOR STUFF, THE NON-MYLEN IS THE DARK COLOR STUFF. SO MORE GRAY MATTER. VERY SYMMETRIC ROBUST PATTERN OF MYELINATION IN BOTH YOUNG SUBJECTS IN BRAIN SLICE, THERE'S LATERAL VENTRICLES WHERE YOU SEE BEAUTIFUL MYELINATION. OLDER CONTROL SUBJECTS THIS IS AN INDIVIDUAL WITH NO COGNITIVE FINDINGS AND YOU CAN SEE AGAIN A DIMINISHED DEGREE OF MYELINATION AS EXPECTED AND ALSO SEEN IN INDIRECT MARKER TYPE METHODS BUT AGAIN VERY NICE SYMMETRY AND BASICALLY FULL PATTERN OF MYELINATION THROUGHOUT THE BRAIN. WITH MCI WE HAVE TWO SUBJECTS WE HAVE COLLECTED A NUMBER MORTIS POINT BUT YOU CAN SEE ASYMMETRY BREAK DOWN OF THE PATTERNS EVEN IN TERMS OF LOCAL HOMOGENEITY IN BOTH SECTIONS, THIS UPPER SECTION AND LATERAL VENTRICLES AND OF COURSE THE VENTRICULAR ENLARGEMENT AS EXPECTED. THIS APPEARS QUITE SENSITIVE TO MYLEN LOSS BECAUSE OF THE WAY EXPERIMENT IS DESIGNED, IT SHOULD HAVE SPECIFIC TO MYELIN LOSS QUITE HAPPY WITH THESE RESULTS. WE HAVE BEEN REQUIRING QUITE A BIT MORE, THIS IS BASED ON SIGNAL SECTION ACCORDING TO THEORY INVERSE PROBLEMS SO I WANT TO MOVE TO ANOTHER MAJOR APPLICATION, A METHOD DEVELOPED OVER SEVEN YEARS AND ARTHRITIS, THIS IS BIGGEST INTEREST OF MY GROUP HISTORICALLY, WHAT IS A WATER POOL? A WATER POOL MEANS WATER ASSOCIATED IN THIS CASE WITH THE THREE MAIN COMPARTMENTS IN CARTILAGE WHICH ARE THE COLLAGEN MACRO MOLECULE ASSOCIATE COMPARTMENT, PROTEOGLYCAN WHICH IS PRESSURE RESISTANT SO THEN WATER WHICH PROVIDES RESISTANCE AND FLOW CAPABILITY. SUPPORTING GLYCAN IS THE MACRO MOLECULE THAT'S LOST FIRST IN OSTEOARTHRITIS. AND CARTILAGE MACRO MOLECULAR STRUCTURE AND FREE WATER THERE. THE DISTINCT POOLS ARE EXPECTED TO HAVE DIFFERENT MR PROPERTIES. SO UNLIKE GETTING A NICE IMAGE JUST CARTILAGE WHICH IS BEAUTIFUL, YOU CAN GO TO YOUR LOCAL SCANNER GET BEAUTIFUL -- IT WILL NOT BE SPECIFIC FOR COLLAGEN PRO OWE GLYCAN OR WATER, IT WILL BE SPECIFIC FOR ALL THE STUFF IN YOUR NEEDS. BEAUTIFUL IMAGE BUT NOT SPECIFIC TO COMPONENTS. WE CAN EXPLOIT THE POOLS USING VARIOUS METHODS AND TRY TO RECAPITULATE THIS IS VISUAL, THIS IS INVASIVE, WE'RE TRYING TO AVOID NEEDING THIS BECAUSE YOU WANT NON-INNOVATIVE QUANTIFYCATION THROUGH THE SOPHISTICATED METHODS OF SIGNAL ACQUISITION AND APPLICATION AND ANALYSIS. SO FOR EXAMPLE, T-2 YOU MIGHT GET A T-2 IMAGE OF A KNEE, THIS IS BEAUTIFUL, YOU CAN SHADIEST THERE, YOU MIGHT HAVE A LITTLE HOLE BUT THAT'S LAID AWAY BY THE TIME YOU HAVE ANATOMIC CHANGE T-2, THE PARAMETER ITSELF IS SENSITIVE TO ALL KINDS OF THINGS IN THE SHIRE SHOE, PULSE SEQUENCE DETAIL, INTERNAL INTERACTION, TEMPERATURE, THINGS WITH NOTHING TO DO WITH OSTEOARTHRITIS, ALSO SENSITIVE TO OSTEOARTHRITIS AND PROTEOGLYCAN BUT YOU SIGH A CHANGE IN T-2 YOU HAVE NO IDEA WHAT YOU'RE LOOKING AT. THIS HAS BEEN A MAJOR IMPEDIMENT IN THE DEVELOPMENT OF THERAPIES FOR OSTEOARTHRITIS IN MY VIEW. ALTERNATIVE AGAIN IS WE DISSECT THE COMPONENTS OF MR SIGNAL SO THAT WE CAN GET MUCH MORE SPECIFIC DATA. THIS IS BEFORE CLINICAL SPOT I WANT TO SHOW YOU A SIMPLE PRE-CLINICAL DEMONSTRATION USING OUR METHODS OF SIGNAL DISSECTION AND PATHOMAGNETIC DEGRADATION, YOU CAN SEE INCREASING PATHOTHIS IS A PROGRESSIVE OA MODEL FOR YOU CAN GET A RATIO OF THE PRO OWE GLYCAN FRACTION TO THE WATER FRACTION FROM YOUR QUANTITATIVE DECREASE IN THE MEDICAL MOLECULE THAT IS MOST READILY LOST IN OSTEOARTHRITIS, THIS IS NOT POSSIBLE FROM A CONVENTIONAL IMAGING SYSTEM. I LOVE THE NEXT TWO SLIDES. I MADE THEM LAST NIGHT, MADE ME QUITE HAPPY. THIS IS SOMETHING WE PUBLISHED IN 2011, THE PROTEOGLYCAN ASSOCIATED WEAR. THE MR SIGNAL, THIS IS THE DISSECTED MR SIGNAL, ONLY A PROTEOGLYCAN, THIS IS EXCISED PARTICULAR CARTILAGE, FIELD STRENGTH VERY HIGH FIELD CONTROL CONDITIONS HIGH RESOLUTION, SENSITIVE PROBE, COMPLICATED MATHEMATICS, A LOT OF WORK AND WE ACHIEVE THIS MAP OF PROTEOGLYCAN ASSOCIATED WATER FIRST ONE, MANY, MANY, MANY GROUPS ARE NOW DOING THIS. WE'RE VERY HAPPY, 2011, SHOWS PROTEOFLY CAN LOST IN OA. THAT WAS THEN AND THIS IS NOW. WE OTHER QUITE HAPPY WITH THE PROGRESSION HERE THIS IS OBVIOUSLY AND IN VIVO STUDY OF PROTEOGLYCAN MAPPING IN THE KNEE, NOT AS BEAUTIFUL AS A STANDARD IMAGE BY PRESSING THE BUTTON ON THE SYSTEM, THAT'S NOT THE POINT. WHEN YOU PRESS THE BUTTON, YOU GET A BEAUTIFUL IMAGE, THIS IS PROTEOGLYCAN SPECIFIC. THIS IS A MAP OF STUFF THAT GETS LOST EARLY IN, OA YOU CAN SEE ALL THIS -- ONE OBJECTION OF THIS STUDY IS THAT'S GREAT, WHAT YOU'RE TELLING ME BUT THE DOTS SHOWING HIGHER PROTEOGLYCAN TOWARDS THE BONE, THAT COULD BE NOISE, NORTORIOUS NOR NOISE DEPENDENT, AS A TECHNICAL POINT WE REPEATED THE IMAGE WITH A TOTALLY SEPARATE SET OF ACQUISITIONS AND WE HAVE IDENTICAL PATTERNS, THIS IS QUITE REMARKABLE SHOWS THIS HIGH RESOLUTION PROTEOGLYCAN SPECIFIC IMAGE ACTUALLY SUCCESSFULLY MAPS PROTEOGLYCAN AND MINIMALLY SENSITIVE TO NOISE. NOW HAVE TO PUT A PLUG IN HERE AGAIN, THIS IS PRETTY ROBUST DATA CONSIDERING THE DIFFICULTY OF THIS PROBLEM AND AGAIN I'M NOT GOING TO TALK ANY MATHEMATICS BUT THE FRANCIS FROM THE PREVIOUS SLIDE ESSENTIALLY THE TRIAL SLIDE SHOWING BONE PARTICULAR CARTILAGE IN HIGH FIELD NON-CLINICAL CONDITION BUT STILL GETTING IMAGES TRANSITION FROM THIS TO THESE WHAT I CALL BEAUTIFUL IMAGES IS REALLY MADE POSSIBLE BY MOVING FROM LINEAR GENOME INVERSE PROBLEM THEORY, I IRE DIGGING INTO SPECIFIC OS OF WHAT'S GOING ON HERE, THIS IS CONVENTIONAL, THIS IS A NOISE PATTERN YOU CAN REPEAT NOISE, AND GET A TOTALLY DIFFERENT VIEW PROTEOGLYCAN, SO BASED ON ANALYSES AND COMPOSITION IS STABLE TO NOISE, HIGHER RESOLUTION AND GIVES REAL HOPE FOR LOOKING AT PROTEOGLYCAN LOSS IN A DETAILED WAY AND PRE-ANATOMICALLY DISTORTED OSTEOARTHRITIS, ANOTHER IMPORTANT THINGS WE CAN USING TO STABILIZE THE METHOD IS THE STATISTICAL LAB, I HAVE SHOWN YOU THOSE, THIS COMES OUT THE SCANNER HIGH RESOLUTION, HIGH SPEED, WHOLE BRAIN CARTILAGE, QUITE A TRIP, WE'RE HAPPY WITH IT. IT COULD BE BETTER. FILTERING -- THAT IMPROVES THE SIGNAL TO NOISE BUT DECREASE IT IS SIGNAL TO NOISE. THISES THE BLURRY FILLER YOU CAN SEE THE SIGNAL TO NOISE IS INCREASED IN THIS IMAGE COMPARED WITH THIS. THIS IS WHAT EVERY INCLUDING US SIGNAL TO NOISE. YOU CAN DO GALSION AVERAGING WHICH AGAIN BLUR PIXELS BUT IN A WAY SLIGHTLY MORE WEIGHTED TOWARDS THE PIXEL OF INTEREST. PLEASE APPRECIATE THE SIGNAL TO NOISE IS BETTER THAN IT IS IN THE ORIGINAL LOWER RIGHT SIGNAL TO NOISE BETTER THAN UPPER LEVEL. BLURRING NOT AS BAD AS LOWER LEFT BUT STILL SIGNAL TO NOISE IS NOT AS GOOD, THERE'S QUITE A BIT OF BLURRING SO WE HAVE DEVELOPED A SO CALLED ESTIMATION MULTI-SPECTRAL MAGNITUDE FILTER BASED ON SOME OF THE SAME MATHEMATICS IN SIGNAL DISSECTION PROBLEM WHICH IS MOW THIS IS RELATED METHOD LOGICALLY AND WE HAVE A VERY NICE IMAGE WITH COMPARED WITH THE ORIGINAL WITH HIGH SIGNAL TO NOISE AND VERY ESSENTIALLY ABSENT BLURRING. SO THIS IS A KIND OF WORK THAT ALSO MAKES THE OTHER STUDIES POSSIBLE. THESE NICE FILTERING METHODS THAT ARE NOVEL AND NOW PUBLISHED. I WANT TO CHANGE COURSE A LITTLE BIT FROM THE IMAGING CAPABILITIES OF MR TO SPECTRA SCOPIC CAPABILITIES. I WANT TO SUMMARIZE A COUPLE OF STUDIES BY DR. FERRUCCI OUR SCIENTIFIC DIRECTOR LOOKING AT MITOCHONDRIAL SCALE AND MUSCLE, WE'RE DOING NON-INVASIVE HISTOLOGY AN BIOCHEMISTRY, THIS IS DOING NON-INVASIVE MUSCLE ANALYSIS. WE LIKE TO DO CORRELATIVE STUDIES WITH INNOVATIVE MUSCLE BIOPSY BUT THE GOAL IS TO LOOK AT IMPORTANT QUALITIES WITHOUT HAVING TO CHOP INTO SOMEBODY'S MUSCLE, IT'S CONSIDERED VERY QUAINT TO DO IT THAT WAY, SO MR IS A SPECTRA SCOPIC METHOD OPPOSED TO IMAGING METHODS THAT ALLOWS QUANTIFICATION OF VERY IMPORTANT METABOLITES ATP PHOSPHATE AND NPH. THIS IS A PICTURE OF THE DATA WE GET, THESE ARE CALLED SPECTRA WHICH MEANS SOMETHING SIGNAL DISTORTED ALONG THE X AXIS BY -- ENERGY IS ON THE X AXIS BUT THIS IS A SPECTRAL POSITION AND AMPLITUDE IS EXPRESSING THE MOIETIES SEEN SO FOR EXAMPLE THIS IS IS ORGANIC PHOSPHATE, THESE ARE THREE PHOSPHORUS ATP. THIS IS PRE-EXERCISE YOU CAN SEE A NICE BIG PCR PHOSPHATE OR PHOSPHOCREATINE, THE DEGREE OF DEPLETION IS SOMETHING WE CAN OBSERVE DIRECTLY, AND THAT IS RELATED TO THE INDIVIDUALS HEALTH WHICH BIOENERGETICS ARE STRESSED BECAUSE OF THE EXERCISE T. THIS IS A RESULT OF THINGS LIKE INTRINSIC MUSCLE FUNCTION AND BIOENERGY CAPABILITY AS WELL AS BLOOD FLOW, SO THIS IS AN INTEGRATED VIEW OF THIS DECREASE IN CRE PHOSPHATE ISN'T ANY WAY MUSCLE HEALTH, WE WANT TO STUDY MITOCHONDRIA, HOW IT GOES DOWN HOW IT GOES UP WITH THE MUSCLES AT REST, THERE'S MANY FEWER CONFOUNDERS SO INSTEAD OF LOOKING AT THE DOWNWARD PART IN RESPONSE TO EXERCISE, LOOK AT RECOVERY PHOSPHATE AFTER EXERCISE, THIS IS A NICE SET OF STAT SPECTRA SHOWING THE CONTROL REST PERIOD EXERCISE SHOWING DEPLETION OF FOE FOE CREATINE, THE RATE OF RECOVERY. THIS RATE OF RECOVERY, PLOTTED OBVIOUSLY IN TWO DIRECT DIMENSIONS WE CAN FIT INTO STANDARD EXPONENTIAL FORM AND COME UP WITH VALUE CALLED TAU FOR A TIME CONSTANT. IS TO THE TIME CONSTANT IS THE ULTIMATE OUTCOME MEASURES IN THE SPECTRA STUDIES, TAKU LONG TIME TO RECOVER, SHORT TAU IS SHORT TIME TO RECOVER. SO YOU WANT TO HAVE SHORTER TAU. THERE SHOULD BE RECIPROCAL SIGN HERE WHICH IS MISSING, I APOLOGIZE TAU IS ONE OVER THIS REACTION RATE. WE LOOKED AT A STUDY INITIALLY LOOKING AT THE BETA CO-EFFICIENTS OR SLOPES OF RELATIONSHIP BETWEEN THIS RECOVERY FUNCTION WHICH INDICATE MITOCHONDRIAL CAPABILITY AND OUR STANDARD WALKING TASK, THIS IS THE MOST BENIGN TASK, IT'S SHORT AND WHATEVER PACE YOU FEEL LIKE GOING THIS IS THE HARDEST ONE, 400-METERS IS QUITE LONG, THIS IS MORE OF A GET MOVING, FAST, FAST, FAST, THE OTHER TWO IN BETWEEN. YOU CAN SEE IT'S QUITE INTERESTING THAT THERE'S OOH MUCH MORE OF A CORRELATION BETWEEN THE TAU, THE RECOVERY RATE OF MITOCHONDRIAL FUNCTION T AND THE FAST PACE, THIS IS WHAT YOU MIGHT THINK IN A LIMITED CASE IF YOU HAVE SOME MITOCHONDRIAL LIMITATION, THIS IS WHAT YOU EXPECT MORE STRESSFUL WALKING TASK WOULD UP COVER THAT POTENTIAL LACK OF PHYSIOLOGIC POTENTIAL OR CAPABILITY THAT'S UNDERLYING MUSCLE FUNCTION. SO THIS WAS PUBLISHED WITH A VERY NICE RESULT. WE HAD THE IDEA OF LOOKING AT MUSCLE STRENGTH AS A POSSIBLE MEDIATOR BECAUSE MUSCLE STRENGTH ALSO DECLINES ALONG WITH MITOCHONDRIAL FUNCTION BUT IT'S UNCLEAR EXTENT WHICH THESE ARE INDEPENDENT PREDICTORS OF PERFORMANCE ON THE WALKING TASK. SO WHEN WE USE FORMAL MEDIATION ANALYSIS INCORPORATING MUSCLE STRENGTH WE FOUND A DECREASE IN CORRELATION OF ALL OF THESE AS EXPECTED YOU CAN SEE IN THIS TEST STATISTICALLY SIGNIFICANT DECREASE IN BETA CO-EFFICIENT CERTAINLY DECREASE BUT NOT STATISTICALLY SIGNIFICANT IN THE SIMPLEST MEASURE BUT MAINTAIN THE STATISTICALLY SIGNIFICANT BETA CO-EFFICIENT INCORPORATENB–D MUSCLE STRENGTH. THERE'S FROM THIS MUSCLE STRENGTH MEDIATES THE AFFECT OF MITOCHONDRIAL FUNCTION ON WALKING PERFORMANCE THIS IS AN INTERESTING NEW RESULTS THIS CAME FROM FROM FERRUCCI'S CONCEPT OF APPLICABILITY OF NMR SPECTROSCOPY. SO I WILL GO THROUGH THE OTHER HIGHLIGHTS, AS A SAMPLE OF WHAT WE CAN DO IN THE LAB, THIS IS WORK WITH DR. EAGAN'S LAB, LOOKING AT DEVELOPMENT OF FATTY LIVER IN TRANSGENIC MOUSE WHICH EXHIBITS ATROPHY IN WHICH THE SUBCUTANEOUS TISSUES IS INACCESSIBLE THE FAT. THISES A WILE TYPE, THIS IS TRANSGENIC ANIMALS, THIS IS ANOTHER SPECTROSCOPY, LET'S LOOK AT WATER AND FAT. YOU CAN SEE HERE THERE'S A GREAT DEAL MORE FAT IN SPECTRUM OBTAINED FROM THIS LIVER THAN FROM THE SPECTRUM OF LIVER FROM THE CONTROL ANIMAL THIS IS SOMETHING WE CAN DO SPECTROSCOPICALLY AND ALSO MONITOR RECOVERY, TREATMENT OF THIS. SO THIS IS AN INTERESTING TARGET OF THERAPY AND IT WAS FOUND IN DR. EAGAN'S LAB, WE PROVIDED IMAGING SERVICES, REVERSE THE DEVELOPMENT IS SIGNIFICANT DEVELOPMENT OF FATTY LIVER, THIS IS A YOUNGER ANIMAL DEVELOPING THE FAT IN THE LIVER HIGH PER TROPHY AND AFTER TWO WEEKS OF LEPTON, THE SIZE HAS DECREASED AS HAS THE FAT CONTENT SO THIS IS A NICE EXPERIMENT, BUT A SUITABLE APPLICATION FOR IMAGING. SO COUPLE OF HYL LIGHTS WE'RE DOING QUITE A BIT OF LIPID MEASUREMENT IN THE HUMAN AS WELL. 3T YOU GOT A CLINICAL SYSTEM BY DR. FERRUCCI FOR CLINICAL TRANSLATIONAL APPLICATION, IT'S VERY EFFECTIVE. THIS IS AGAIN A PROTON SPECTRUM OF THE SIDE WHERE WE SEE CELLULAR LIPIDS WHICH ARE VERY METABOLICALLY ACTIVE AND OTHER KNOWN METABOLITES. THESE ARE NOT THE REAL POINT OF THIS, JUST TO SHOW WHERE THE IMAGES ARE TAKEN, HOW WE ACQUIRE THE DATA, AND WE'RE DOING QUITE A BIT OF CORRELATIVE STUDIES OF THIS. ANIMAL MODELS, THIS IS STROKE IN A RAT MODEL LOOKING AT RATS, HIGH FAT DIET IN COLLABORATION WITH -- WE DO SEE DEVELOPMENT OF STROKE. AND ALSO WE CAN DO CARDIAC IMAGING IN MICE. THE VENTEDCLE IS THICKER, THE -- WHILE LEFT VENTRICLE DIASTOLE AND SYSTOLE, HERE IS LEFT VENTRICULAR LIDS MUCH THICKER IN SYSTOLE THAN DIASTOLE. IT MAINTAINS THICKNESS THROUGHOUT AS EXPECTED YOU CAN SEE A NICE LINEAGE LV RD AND YOU CAN HAVE IMAGES SO THAT WAS A LITTLE BIT OF A SUMMARY WHAT MY GROUP WAS DOING T I WANT TO MOVE TO DR. EAGAN'S GROUP, ABOUT WHICH I KNOW LESS. HER GROUP IS METABOLIC FUNCTION GLUCOSE HOMEOSTASIS, ALL COMPLEX TRAITS INVOLVING ENTIRE NETWORKS EFFECTED NOT JUST BY AGE BUT GENETIC ENVIRONMENTAL PERTURBATIONS. SO THE SECTION IS TAKING INTEGRATED APPROACH ACROSS A VARIETY OF MOW DAMTIES TO LOOK AT CHANGES IN SUPPORT OF HORMONAL PATHWAYS. TWO SAMPLES ARE THE GLUCAGON TYPE 1 AND ENDOCANNABINOID AXIS. THIS IS A COMPREHENSIVE APPROACH, COLLECTED FROM A NUMBER OF METABOLICALLY ACTIVE ORGAN SYSTEMS INCLUDING SYSTEMS NOT PREVIOUSLY BEEN INVESTIGATED IN THIS WAY, AGAIN LONG TERM GOAL GOAL DEVELOPING THERAPEUTIC. GLP 1 IS NOW A TARGET FOR TREATING DIABETES, DEVELOPED IN HER LAB AND AGAIN MULTIPLE LEVELS OF ORGANIZATION AND SOME OF THE ENTER-- AN EXPANSION OF THE ENDO-- INTERACTION TABLES MEDICAL SCHOOL, IT HAS GOTTEN MUCH MORE COMPLICATED. ANOTHER IMPORTANT AREA THAT SHE'S WORKING ON IS THE CANNABINOID 1 RECEPTOR IN THE BRAIN, THE MOST PREVALENT G PROTEIN COUPLED RECEPTOR SYSTEM IN THE BRAIN. THESE WERE DEVELOPED AS MEDICAL THERAPIES 20 YEARS AGO BUT THIS ENTIRE CATEGORY SUFFERED AHEAD WHEN (INAUDIBLE) WAS DISCONTINUED FROM THE MARKET BECAUSE OF POSSIBLE LIFE THREATENING PSYCHIATRIC PROBLEMS SO THAT'S NOT GOOD. AS AN AL TERMTIVE TO THIS WHOLE BODY WORK, PERIPHERAL ACTIVITY OF THE ENDOCANNABINOID SYSTEM AND PERIPHERAL ACTIVITY AND DESIGNING PERIPHERALLY ACTIVE SPECIFIC RECEPTOR LIGAND SO FOR EXAMPLE, LOOKING AT TISSUE SPECIFIC CANNABINOID 1 BLOCKERS TARGETED TO BETA CELLS HE HAT SITES TO INCREASE INSULIN SECRETION. THE GOAL HERE IS TO DEVELOP THERAPIES FOR AS SPECIFICS OF ALCOHOLIC LIVER DISEASE, FATTY LIVER, CERTAIN SPECIFIC CASES OF OBESITY, SYNDROME IS REALLY CONGENITAL DISORDER, GENETIC DISORDER THAT HAS MANY ASPECTS TO IT ONE WHICH IS OVEREATING AND OBESITY. ALSO,FATTY INFILTRATION AND DIABETES RUNNING THE BIOCHEMICAL DRUG SCREENING JUNE AND HAVE BEEN MOTIVATED BY KETAMINE AS ANALGESIC/ANESTHETIC AND ANTI-DEPRESSIVE, THIS HAS RECEIVED PRESS LATELY, IT WAS FOUND PLASMA LEVELS OF KETAMINE AND NEUROKETAMINE DIDN'T CORRELATE WITH THERAPEUTIC RESPONSE. IT'S -- DRUG IS EFFECTIVE BUT DIFFICULT TO QUANTIFY THE DOSE RESPONSE SECTION SO THE SEPARATE WAS DEVELOPED TO SEPARATE KETAMINE FROM ITS FULL SET OF DOWNSTREAM METABOLITES. AND SUCCESSFUL EXPERIMENTS SHOWED THAT THE THESE 2R 6R SUCCESS A COMBINATION WITH TWO INTERMERES IS A MAJOR METABOLITE IN HUMANS AND FOUND THAT ANTI-DEPRESSIVE EFFECT IN ANIMAL MODEL SO FOR A KETAMINE SYSTEM IT WAS DOWNSTREAM METABOLITE FOUND QUANTITATIVELY LINKED TO THIS THERAPEUTIC EFFECT. SO THIS IS PATENTED BY THE NIH AND DEMONSTRATED TO HAVE ANTI-DEPRESSIVE EFFECTS IN MICE AND FURTHER PRE-CLINICAL WORK IS CONTINUING WITH THIS VERY IMPORTANT COMPOUND. THIS SECTION ALSO PERFORMANCE PROTEOMIC METHODS IN SUPPORT OF OTHER PROJECTS AND ME AT THAT TIME LOAMIC ASSAYS SHOWN HERE. FINALLY LIPID MEDIATORS LED BY TALENTED CLINICAL INVESTIGATOR CHRISTOPHER RAMSDEN. HIS CAREER IS BASED ON THE FACT SO MANY INDIVIDUALS TAKE ANALGESICS ON A REGULAR BASIS, THIS OBVIOUSLY HAS SIDE EFFECTS WHICH I DON'T NEED TO GO THROUGH DEPENDING ON ANALGESIC SO HE'S LOOKING CLOSELY AT -- (INDISCERNIBLE) (INDISCERNIBLE) POST TRAUMATIC HEADACHE, PARTICULAR PAIN AND OTHER SETTINGS. NOW HE'S NOW MOVING INTO MOLECULAR MECHANISMS LINKING MEDIATORS LOOKING AT ENDOGENOUS LIPID MEDIATOR OF INFLAMMATION AND PAIN AND FURTHER MECHANISTIC STUDIES TO CHARACTERIZE THESE. AND THAT IS THE SUMMARY. THANK YOU VERY MUCH. [APPLAUSE] >> ANY QUESTIONS FROM COUNCIL MEMBERS? YES. >> I HAVE A QUESTION ABOUT THE TECHNIQUE YOU USE TO ASSESS MYELIN IN THE BRAIN, DIFFUSION SENSOR IMAGING IS SEPARATE TECHNOLOGY RELATED TO WHAT YOU'RE SHOWING BUT WHAT ARE THE POTENTIAL ADVANTAGES OF WHAT -- THE WAY YOU'RE DOING THIS VERSUS USING DTI TO ASSESS THE WHITE MATTER QUANTITATIVELY? >> THIS IS A GREAT POINT, GREAT QUESTION. SO DTI DIFFUSION TENSOR IMAGES IS SENSITIVE TO THE DIRECTIONALITY OF FIBERS IN THIS CASE MYELIN FIBERS ALSO USED IN MUSCLE IN OUR LAB. THE ISSUE IS TO DEVELOP OUR GOAL IS TO DEVELOP SOMETHING QUANTITATIVE SO WHEN THE STRENGTH CHANGES BY FACTOR OF THREE QUARTERS THAT MEANS THE MYLEN CHANGED BY A FACTOR OF THREE QUARTERS. DTI DOESN'T HAVE THAT CAPABILITY, G2 DOESN'T HAVE THAT CAPABILITY, THOSE THAT HAVE CAPABILITY IS A DIRECT MEASURE OF MYELIN SO THAT'S THE MAIN DIFFERENCE. IT'S A VERY IMPORTANT DISTINCTION YOU'RE MAKING, GOOD QUESTION. >> OTHER QUESTIONS? >> I WAS GOING TO ADD SOMETHING SIMILAR TO WHAT DAVE SAID. I HAVE BEEN REALLY DISAPPOINTED WITH WHAT DTI HAS SHOWN PARTICULARLY EARLY IN T DISEASE SO -- WALKED BACK IN, I WONDER IF BECAUSE YOU DON'T SEE MYELIN CHANGES YOU HAVE TO WAIT FOR THE NEURONS TO DIE. AND DO YOU FEEL LIKE YOU'RE ACTUALLY PICKING UP SOME ACTUAL CHANGE IN MYELIN RATHER THAN LOSS OF NEURAL PILL MORE GENERALLY? I'M ASKING IS THERE SPECIFIC SIGNAL OF LOSS OF MYELIN IN NEURODEGENERATIVE DISEASE THAT YOU THINK YOU'RE PICKING UP ABOVE AND BEYOND WHAT THE UTI HAS FAILED TO SHOW? >> THAT'S THE THESIS OF THIS WORK. AND IT'S QUITE HARD TO CONFIRM THAT, THOUGH WE'RE WORKING ON THIS. SO IT'S VERY, VERY BRIEFLY, I WILL SIMPLIFY THINGS AS APPROPRIATE, MY OWN BRAIN KEEP THINGS SIMPLE, THERE'S WATER IN THE BRAIN ASSOCIATED WITH MYELIN AND WATER NOT ASSOCIATED WITH MYELIN, THEY HAVE DIFFERENT MR CHARACTERISTICS BUT THEY CONTRIBUTE TO THE SIGNAL, THAT'S WELL KNOWN BENCH TOPIC AND ANIMAL EXPERIMENT SO THE SIGNAL IS CONSISTS OF CONTRIBUTIONS FROM BOTH COMPONENTS. WE CAN DISSECT THAT SIGNAL WHICH IS WHAT WE HAVE BEEN DOING, BUT WE CAN HAVE -- SEPARATE THE SIGNAL OUT FROM MYELIN. THE POINT IN FACT IS THAT SIGNAL REALLY IS THE MYELIN SIGNAL AS OPPOSED TO SOMETHING THAT IS RELATED TO MYELIN SUCH ADS MOBILITY OR DIRECTIONALITY OR FIBER INTEGRITY, IT'S NONE OF THAT, IT TEASE MYELIN SIGNAL ITSELF WHICH IS WHY THIS IS -- WE FEEL THIS IS OF INTEREST IN CONTRAST TO THE OTHER USEFUL BUT INDIRECT MEASURES OF MYELIN, THAT ALSO HOLDS POTENTIAL FOR EARLY DETECTION FOR OBVIOUS REASONS. S >> THANK YOU VERY MUCH, DR. SPENCER. DR. ED LAKATTA WILL DESCRIBE CARDIOVASCULAR, CARDIO LAB. OOZE TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST TEST >> WE'RE GOING TO SWITCH GEARS AND TALK HEART RATE. IT'S HEART BREAK OF AGING AND WE WILL START OFF WONDERING WHY DO WE STUDY AGING. SO WHAT HAPPENED? GENERAL AGING EXPECTS CHAOS FOR MORTAR. THE MOLECULAR DISORDER LEADS FIRST TO LOSS OF OUR RESERVE FUNCTIONS. THESE ARE ARBITRARY FUNCTIONS THAT ARE CHANGING WITH INCREASING AGE, THEY CHANGE AT DIFFERENT RATES, SOME OF THEM ACTUALLY CAN GET BETTER TEMPORARILY. DISEASES BEGIN TO MAKE THE SCENE AND VECTOR FUNCTION IS ON THIS RED LINE AND THE COMORBIDITY ISSUES ARE WELL KNOWN TO BE OCCURRING HERE. THIS DASH LINE IS THE RESTING LEVEL AND WHEN OUR FUNCTIONS DROP BELOW THAT, THEY CALL US FRAIL. I PROMISE YOU A TALK OBJECT HEART. -- ON THE HEART. SO WE'RE GOING THE TALK MANLY ABOUT THE INITIATION OF THE HEART BEAT, IT STARTS UP HERE IN THE RIGHT ATRIUM BETWEEN THE SUPERIOR VENA CAVA AND THE ENFEAR YOUR VENA CAVA WHERE THE BLOOD IS BRINGING CHEMICAL INFORMATION MECHANICAL INFORMATION, ET CETERA, FROM THE WHOLE BODY. AND THE IMPULSE THEN TRAVELS DOWN TO THE VENTRICLE HERE WHICH EXECUTE THE HEART BEAT BY CAUSING A CONTRACTION SO THE ASINOATRIAL NODE IS PROBLEMATIC. THIS SHOWS A FEMALE AND MALE NUMBER OF PATIENTS WITH SINOATRIAL NODE DISEASE AS A FUNCTION OF AGE. THE NATURE OF THIS DISEASE IS HETEROGENEOUS. THERE'S A BEATING TOO SLOW, SLEEPING IF YOU WILL, BETWEEN BEATS. SINUS ARREST. SINOATRIAL NODAL EXIT BLOCK IF IMPULSE CAN'T GET OUT OF SINOATRIAL NODE. SIX SINUS SYNDROME AND TACKY BRADY SYNDROME, ALL CONFUSED GOING FAST BUT SOMETIMES THEN GOING SLOW AND THIS IS A PRECURSOR OF ATRIAL FIBRILLATION WHICH IS A BIG PROBLEM IN OLDER PERSON. THE END GAME THOUGH IS LARGE NUMBER OF PEOPLE WORLDWIDE HAVE A PERMANENT PACEMAKER IMPLANTED. OVER 80% IMPLANNED OCCUR IN OLDER PERSONS. THE TOTAL COST IN OUR COUNTRY ALONE IS $24 BILLION. THAT WAS IN 2010, IT'S PROBABLY MORE THAN THAT NOW. SINOATRIAL NODAL DISEASE IS THE MOST COMMON INDICATION FOR INSERTION OF PACEMAKER THAT ACCOUNTS FOR 50% OF THE IMPLANT AND IT DOESN'T DO ANYTHING FOR THE DISEASE, IT JUST TREATS SYMPTOMS. WE LIKE TO START WITH HEALTHY OLDER PEOPLE, I WANT TO SHOW YOU EVEN IN YOU NOW AS YOU SIT HERE, THINGS ARE HAPPENING, YOUR HEART FUNCTION AND THE WAY YOUR PACEMAKER WORKS. I WILL SHOW YOU RESULTS OF 30 YEAR STUDY WE DID TO LOOK AT RESERVE FUNCTION IN THE BALTIMORE LONGITUDINAL STUDY ON AGING, IN THAT STUDY PEOPLE COME IN AT DIFFERENT AGES AND STAY FOR DIFFERENT PERIODS OF TIME AND WE MAKE INITIAL MEASUREMENTS AND THEN REPEATED MEASUREMENTS OVER TIME AS LONG AS THEY'RE IN THE STUDY. THE RATE OF THE SLOPE OF THESE SPAGHETTI STICKS IF YOU WILL IS THE RATE OF AVERAGE, THE AVERAGE RATE OF DECLINE FOR PEOPLE THAT COME IN AT STARTING AGE, THIS SHOWS THE RATE OF DECLINE IN EACH INDIVIDUAL WITH REPEATED MEASUREMENTS. YOU CAN SEE PER DECADE WE LOSE 10 BEATS, THE SCATTER IS NOT VERY MUCH, THIS IS VERY TIGHT, THIS IS INEVITABLE, THIS IS THE ONLY -- ONE OF THE ONLY GOOD-BYE MARKERS OF AGING THAT I KNOW ABOUT AND IT CAN'T BE REMEDIED BY ANYTHING WE KNOW NOT EVEN PHYSICAL CONDITIONING PEAK HEART RATE, HAPPENS IN FLIES, ROOM TEMPERATURE, FLIES HEATED UP, THIS IS HUMAN DATA. WHY IT CAN'T BE OLDER HEART BEAT AS THE YOUNGER HEART? WE KNOW THERE ARE MULTIPLE INPUTS TO THE SINOATRIAL NODE WHICH IS HERE, MANY OF THEM COME -- IT WILL BEAT BY ITS OWN ON ITS OWN IF THE HEART IS TAKEN OUT OF THE BODY BUT SIGNALS COME THROUGH THE BRAIN TO MODULATE THE BEATING RATE AND THE BRAIN GETS SENSORY INPUT TO KNOW SIGNALS TO SEND FROM THE HEART FROM LUNGS TO COMPOSITION OF BLOOD TO SENSES, ET CETERA. THIS SHOWS THE AUTONO, MA'AMIC INNERVATION OF THE HEART THE VAGUS TO THE SINOATRIAL NODE AND SYMPATHETICS AND ANOTHER MAJOR INPUT COMES FROM THE ADRENAL GLAND, EPINEPHRINE, WHICH HELPS TO MAKE THE, THIS SHOWS WHAT HAPPENS DURING EXERCISE AS THE HEART RATE GOES UP AND WORKLOAD INCREASE, PLASMA, EPINEPHRINE AND NOREPINEPHRINE INCREASES SO WOULD THIS BE A PROBLEM WITH OLDER AGE OLD WHY CAN'T THE HEART BEAT SO FAST? THIS SHOWS THE LEAST SQUARES LINEAR REGRESSION ON AGE PLASMA EPINEPHRINE AND NOREPINEPHRINE AT REST AND AT DIFFERENT GRADES ON THE TREADMILL, THESE ARE SIGNIFICANT SLOPES SHOWING THE OLDER PERSONS ELABORATE MORE CATECHOLAMINES DURING STRESS. SO THIS SUGGESTS THAT THE RESPONSE TO THE CATECHOLAMINES IS NOT AS GOOD AS IT SHOULD BE AND THIS IS A STUDY WE BEGAN SOME STUDIES, THIS IS A CATALOG OF A 40 YEARS EXPERIMENT I'M GOING TO TELL YOU ABOUT ONLY POSSIBLE IN AN ENVIRONMENT LIKE THE INTRAMURAL RESEARCH PROGRAM. WE DISCOVER NEW THINGS AS WE GO AND APPLY TO AGING BUT THIS WAS JUST AN INFUSION OF BETA ADRENERGIC AGONIST TOLL YOUNGER AND OLDER PERSONS, YOU SEE IT SHIFT DOWNWARD IN THE RIGHT IN THE OLDER PERSONS SO WE WANTED TO HAVE A LONGITUDINAL STUDY IN MICE TO LEARN MORE ABOUT THE MECHANISM AND SEE IS MOUSE IS A GOD EXAMPLE FOR AGING. ALL THESE MICE WRITTEN TO THE STUDY AT THE SAME AGE AND WE FOLLOW THEM UNTIL THEY DIE. THEREFORE WE CAN TRACE DATA ON EACH MOUSE BACK OVER THE LIFE SPANKER THIS IS THE MORTALITY CURVE, THE MEDIAN MORTALITY WAS 24 MONTHS, WE REFER TO THOSE FOR THIS REGULARS SHORTLY, IF THEY LIVE LESS THAN MEDIAN AND LONG LIVED IF THEY LIVE LONGER THAN THE MEDIUM. SO LET'S LOOK AT THE HEART RATE DATA FROM THE STUDY, THIS IS THE CROSS SECTIONAL, THIS IS THE WAY AGING RESEARCHERS REPORT IN THE LITERATURE. YOU HAVE DIFFERENT ANIMALS AT DIFFERENT TIME POINTS AT DIFFERENT AGES, AND THE NUMBER OF CHANGES IN THIS COHORT BECAUSE SOME ARE DYING AS YOU GO UP TO MEDIAN LIFE SPAN. THESE ARE SHORT LIVED ANIMALS WHO ONLY LIVE TO THIS POINT, THESE ARE LONG LIVED ANIMAL SO UP TO THIS COMMON MEDIAN LIFE SPAN POINT THE HEART RATE IS SLOWER THAN THOSE GOING TO LIVE LONGER. LOOK WHAT HAPPENED AFTER THIS? DRAMATIC REDUCTION IN THE HEART RATE. HOW MUCH IS DUE TO AUTONOMIC NERVOUS SYSTEM IN THE MOUSE? IF YOU BLOCK THE AUTONOMIC NERVOUS SYSTEM WE CALL THAT THE INTRINSIC HEART RATE AND THE INTRINSIC HEART RATE UP TO THIS COMMON SURVIVAL POINT DOES NOT DIFFER IN THOSE MICE THAT ARE GOING TO LIVE LONGER ON THIS POINT AND THE ONE WHOSE DIED PRIOR TO THIS. NOW LOOK. THIS IS THE ESSENCE OF THE PROBLEM WITH AGING. THE INTRINSIC FUNCTION OF SINOATRIAL NODE COMES MARKEDLY REDUCED WITH AGING, LOOK AT THE AUTONOMIC INPUT THIS IS THE SHORT LIVED HEART RATES HERE, SHORT LIVED MICE THESE ARE THE LONG LIVED ONES. AND THE DIFFERENCE BETWEEN THE TWO CURVES GIVES US AN ESTIMATE OF THE AUTONO, MA'AMIC INPUT. YOU CAN SEE THE NET INPUT HERE SYMPATHETIC BECAUSE IT'S DRIVING THE HEART RATE TO BE FASTER. AND YOU SEE WHAT'S HAPPENING HERE THE DIFFERENCE IN LATE LIFE AND THAT'S SHOWN HERE. THERE IS A SYMPATHETIC SURGE THREE MONTHS OR SO BEFORE DEATH. THE SHORT LIVED HERE AND LONG LIVED THE PROBLEM IS EVEN IF ANIMALS ARE LAS VEGASSING LONG SINOATRIAL NODES ARE IN SUCH POOR CONDITION THEY DON'T RESPOND WELL AS THEY SHOULD TO SYMPATHETIC STIMULATION. WHICH IS SHOWN HERE, THE DOSE RESPONSE CURVE TO THIS BETA ADRENERGIC SHIFTED. SO WE HAVE TO KEEP ASKING WHY. SO WE HAVE TO GO TO CELLS, IT TOOK US A LONG TIME TO ISOLATE, WE TRACKED OVER TEN YEARS TO BE ABLE TO DO IT. ISOLATE CELLS FROM THE SINOATRIAL NODE OR VENTRICLE, THESE ARE VENTRICULAR MYOCYTES, THEY'RE NICE BEAUTIFUL THINGS TO LOOK AT, EASIER TO ISOLATE, THE SCRANY GUYS HERE ARE THE SINOATRIAL PACEMAKER CELLS THAT ARE RESPONSIBLE FOR PROMPTING INITIATION OF THE HEART BEAT. THESE CELLS HAVE SPONTANEOUS DIASTOLIC BETWEEN ACTION POTENTIALS. SO THE WORLD OF PACEMAKER PHYSIOLOGY FUNCTIONS ON WHAT'S GOING ON THERE. WE HAVE TO CONSIDER THAT THE NUMBER OF MYOCYTES IS DECREASING WITH AGE AS WELL, THIS IS ANOTHER PROBLEM BUT OUR WORK FOCUSES ON THE CHARACTERISTICS OF THESE CELLS SO IN OTHER WORDS WE ASK WHAT'S IN THE BOX. WE STARTED THIS WORK 1998. WHEN WE ENTERED THE FIELD, IT WAS DOMINATED BY ELECTROPHYSIOLOGISTS WHO BELIEVE THE BEGINNING AND END OF PACEMAKER FUNCTION WAS IN THIS ENSEMBLE OF ELECTROGENIC MOLECULES EMBEDDED IN THE CELL MEMBRANE, WE HAVE BEEN STUDYING CALCIUM CYCLING IN VENTRICULAR MYOCYTES FOR 22 YEARS AND BUILT SOPHISTICATED APPARATUS TO DO NANOSCALE MEASURES, ET CETERA, WE THOUGHT THIS WAS THE CALCIUM CLOCK AND LATER THEIR MOLECULES MEMBRANE CLOCK OUR WORK THEN HAS SHOWN THAT A PACEMAKER CELL FUNCTION RESULTS FROM A SYSTEM OF CHEMICAL AND ELECTRICAL CLOCKS THAT MUST WORK TOGETHER FOR PROPER FUNCTION. LET'S LOOK INSIDE THE PACEMAKER CELL. THE IMMEDIATE BIOLOGIC CALCIUM SIGNAL OF A PACEMAKER IS TIMING AND AMPLITUDE OF SPONTANEOUS LOCAL SIGNALS DURING DIASTOLE. DOESN'T WORK -- OKAY. I HAVE TO SHOW YOU THE REAL MCCOY, THIS IS AN ACTUAL CELL, YOU SEE THE THINGS YOU SEE THIS, THEN YOU WILL SEE THINGS GET BRIGHT. REAL ESSENCE OF WHAT'S GOING ON IS IN THIS. SO THE RIGHT IS THE BLUE CURVE HERE IS THE ACTION POTENTIAL. THIS IS A CELL LOADED WITH A CALCIUM INDICATOR AND FOLLOWING THE ACTION POTENTIAL THIS CALCIUM TRANSIENT WHICH IS A WHOLESALE TRANSIENT OCCURS, THESE -- I WANT TO CALL ATTENTION TO GENERATING THIS SIGNAL IN DIASTOLE AND WE'LL COME BACK TO THIS. HOW DOES A CALCIUM CLOCK KEEP TIME? IN ORDER TO SEPARATE THE CALCIUM FROM THE MEMBRANE CLOCK WE HAVE TO GET RID OF IT, HOW DO WE DO THAT? PUNCH HOLES IN THE CELL MEMBRANE AND THE CLOCK WORKS ON ITS OWN IF WE PROVIDE THE SUBSTRATE WHICH IS CALCIUM. SO WE GET IMAGES OF THE RELEASES AND WHEN WE DO A SPECTRAL ANALYSIS YOU HEARD DR. SPENCER TALK ABOUT THESE. YOU SEE THE SIGNAL IS ROUGHLY PERIODIC. IN THIS CASE AROUND THREE HERTZ. THIS IS KEY PACEMAKER FUNCTIONS TO MAKE A LONG STORY SHORT THE CALCIUM RELEASES BIND TO CALMODULIN AND THEY ACTIVATE A BRAIN TYPE NLA CYCLASE 8 IN THE HEART, INCREASING PKA AND THE CALCIUM ALSO BINDS TO CALMODULIN ACTIVATES CAN K 2, THIS CAUSES PHOSPHORYLATION OF THE CALCIUM CLOCK. THIS PHOSPHORYLATION IS REALLY KEY BECAUSE IT'S THE REASON WHY THE CLOCK COULD BE RHYTHMIC. # # SO THIS OCCURS FROM REFRACTORY, YOU MOB AFRAID WHAT'S GOING ON IN YOUR HEART THIS IS STOCHASTIC BEHAVIOR PREDICTABLE UNLESS REGULATED. THE REASON IT'S GREAT IS BECAUSE IT CONDITION REGULATED, AND WHEN IT IS IT CAN HAVE INCREASES AN DECREASES IN THE HEART RATE FUNCTION. SO THIS SHOWS THAT PHOSPHORYLATION INCREASES THERE'S NO PHOSPHORYLATION WE HAVE RARE STOCHASTIC CALCIUM SPARKS. AS THIS POST TRANSLATIONAL MODIFICATION INCREASES WE CAN GENERATE RHYTHMIC POWERFUL LOCAL CALCIUM RELEASES THAT PROMPT THE GENERATION OF ACTION POTENTIAL BY THE CLOCK, THIS IS EXPERIMENTAL DATA TO SHOW YOU IN CONTROL THERE'S THE RHYTHMIC SIGNAL WHEN WE INHIBIT WITH A SPECIFIC PEPTIDE INHIBITOR PROTEIN KINASE A, WE HAVE RANDOM BEHAVIOR. SIMILARLY IF WE INHIBIT WITH A SPECIFIC PEPTIDE CALMODULIN KINASE 2, WE CHANGE RHYTHMIC SIGNALS TO RANDOM SIGNALS. THAT SYSTEM I DIDN'T TAKE THE TIME TO TELL YOU THERE'S A PROBLEM BECAUSE IT'S FEET FORWARD, CALCIUM RELEASE WILL ACTIVATE MORE PHOSPHORYLATION WHICH CAUSES MORE CALCIUM RELEASE, BLAH, BLAH, BLAH. SO WE HAD TO GO TO FIND THE BREAKS IN THE SYSTEM AND THE BREAKS OF THE PHOSPHODIE ESTERASES AND THE PHOSPHOPROTEIN PHOSPHATASE, THEY KEEP THIS CYCLING WITHIN THE MID RANGE THIS IS PHOSPHODIE ESTERASE IT DEGRADES SIGH LICK AMP AND THERE'S OTHER PHOSPHATASES HERE. THIS DEPHOSPHORYLATES PROTEIN SO WE'RE KEPT MID RANGE, SO HEART DOESN'T HAVE TO START FROM SCRATCH WHEN IT WANTS MORE CYCLIC AMP BETA RECEPTORS STIMULATED FOR EXAMPLE. WHAT LINKS THE CALCIUM CLOCK BACK TO THE ACTION POTENTIAL CYCLIC -- NOW WE HAVE TO MARRY THE CLOCKS PUT BACK THOSE FUNNY GUYS. THEN WE FIND THAT THESE ION CHANNELS AND ELECTROGENERAL UK MOLECULES IN THE SARCOLE MA ARE MODULATED BY CALCIUM WHICH IS A SIGNAL GENERATED BY CALCIUM CLOCK, MODULATED ALSO BY PHOSPHORYLATION WHICH IS THE SIGNAL GENERATED BY THIS ENGINE INSIDE THESE CELLS. YOU SAW BEFORE, SING IF YOU WANT TO SING. WHEN THE AUTONOMIC RECEPTORS ARE STIMULATED THEY MODULATE THE SYSTEM I WAS TELLING YOU ABOUT, THE INTRINSIC SYSTEM, THE VERY SAME ONE. LET'S LOOK AT BETA ADRENERGIC STIMULATION. NOT ONLY DO THE RATE PICK UP BUT YOU SEE THESE ARE GETTING BIGGER AND BRIGHTER. THERE'S THE CONTROL ON THE LEFT, SAME CELL STIMULATED WITH A BETA RECEPTOR LIGAND. NOW READY TO GET BACK, WHAT ABOUT AGING? WE COULDN'T ASK THESE QUESTIONS UNTIL WE DEVELOP THIS TECHNOLOGY AN LEARN ABOUT HOW THESE CELLS WORK. ONE THING THAT HAPPENS IS THE CALCIUM CLOCK BREAKS SO WE WILL BE SHOWING DATA ON AGING ON THIS CALCIUM CLOCK AND SOME DATA ON REGULATION OF PHOSPHORYLATION OR THE BREAK. THIS IS ISOLATE'S THESE ARE ISOLATED CELLS, NORMAL YOUNG SINOATRIAL NODE, THE BEATING RATE IS LOWER AND CELLS ISOLATED FROM THE OLDER SA NODE. THE CALCIUM CYCLING IS SLUGGISH, RATE OF REMOVAL IS SLUGGISH AND THE AMOUNT RELEASED WITH EACH ACTION POTENTIAL IS REDUCED. SOME OF THE PROTEINS THAT ARE INVOLVED IN CYCLING THERE'S REDUCED EXPRESSION OF THE CALCIUM PUMP, RECEPTOR THAT'S THE CALCIUM RELEASE CHANNEL, THE CALCIUM EXCHANGER WHICH IS THE TARGET RELEASED CALCIUM TO CAUSE INWARD CURRENT, THIS SHOWS RECEPTOR IMMUNOLABELLING BEFORE THE TOTAL RECEPTOR, AND THE MERGED IMAGE NOT ONLY AS THE RECEPTOR NUMBER REDUCED BUT IT'S LESS PHOSPHORYLATED RECEPTOR. IF WE DO THE PERMEABLE SAILINGS AND MEASURE THE RELEASES WE SEE THE CALCIUM SIGNAL GENERATED BY THE CALCIUM CLOCK IS LESS WITH INCREASED AGE HERE. THAT'S BECAUSE THE PUMP DOESN'T WORK SO GOOD AND LOAD OF CALCIUM ON THE SR WHICH REGULATES THE SPONTANEOUS RELEASES IS LESS THAN IN THE YOUNG WHEN WE DO A FREQUENCY ANALYSIS WE SEE THE PREDOMINANT FREQUENCY IN THE OLDER PACEMAKER CELLS IS LOWER THAN IN THE YOUNGER CELLS. WE SEE HERE THAT THIS FREQUENCY IS DEPENDENT ON CALCIUM IN THE SYSTEM, BUT ANY CALCIUM THE FREQUENCY IS BLUNTED THE IN THE OLD AND FURTHERMORE THE NUMBER OF CELLS THAT PERIODIC BEHAVIOR IS REDUCED. YOUR PACEMAKER. FINALLY IF WE TRY TO REMOVE THE BREAKS AS I TOLD YOU, IN THE YOUNG WE SEE A MARKED INCREASE IN CALCIUM SIGNAL THAT'S PROMPTING ACTION POTENTIAL AND WE DON'T SEE AN APPRECIABLE INCREASE IN THE -- THIS SHOWS PHOSPHORYLATION CHANGES AFTER PDE INHIBITION. THE BRIGHT YELLOW IS THE STRONGEST SIGNAL SO THIS IS THE YOUNG AFTER PDE INHI BIG, THIS IS THE OLD CELL. I THINK MAYBE -- TO MAKE A LONG STORY SHORT, WE HAD BEEN STUDYING THE STRENGTH OF THE HEART BEAT LONG BEFORE WE BEGIN TO STUDY PACEMAKER ACTIVITY. THIS IS THE EJECTION FRACTION THE RATE OF CHANGE PER DECADE IN THE DIFFERENT INDIVIDUALS AND STUDY BALTIMORE LONGITUDINAL STUDY ON AGING, IT'S A LITTLE OVER 2% LOSS IN PEAK EJECTION FRACTION PER YEAR. WE TAKE THE CELLS OUT, SO GUESS WHAT, DETERIORATION OF THE SAME MECHANISM IT IS THE PACEMAKER CELLS AND VENTRICULAR MONOCYTES UNDERLIES THE AGE ASSOCIATED DETERIORATION OF THE INITIATION OF THE HEART BEAT AND THE EXECUTION OF THE HEART BEAT. NOT GOING TO SHOW YOU THAT, WE HAVE MADE A LOT OF THOSE DISCOVERIES AS DID A NUMBER OF OTHER LABS IN THE FIELD HOW VENTRICULAR MYOSITES WORK. WE SHOW THAT WITH AGING THE PHOSPHORYLATION OF A LOT OF THESE MOLECULES BECOMES REDUCED. AFTER BETA RECEPTOR STIMULATION. THIS ALLOWS US FINALLY TO CONCEPTUALIZE GENERAL THEORY HOW STRONG AND FAST THE HEART BEAT AND HOW IT AGES. SINOATRIAL NODAL CELLS VENTRICULAR MONOCYTES, PHOSPHORYLATION IS HIGHER AT THE BASELINE IN A SINOATRIAL NODAL CELLS, THAT'S WHY THEY BEAT SPONTANEOUSLY. SO INITIATION OCCURS HERE WITH THE SPONTANEOUS LOCAL CALCIUM RELEASE, THAT DRIES UP THE MEMBRANE POTENTIAL TO OPEN UP THE CHANNELS CALCIUM INFLUX OCCURS. THAT RESETS THE CALCIUM CLOCK THEN THE CALCIUM INFLUX REWINDS SO ACTION POTENTIAL ITSELF RESETS AND REWINDS THE CALCIUM CLOCK, THEN YOU SEE IMPULSE IS CONDUCTED EARLIER DOWN TO THE VENTRICLE. WHEN THE BETA RECEPTORS ARE STIMULATED THERE ARE BETA RECEPTORS HERE TOO SO NOT ONLY SIMULTANEOUSLY SINOATRIAL NODAL CELLS MUST SPEAK FASTER BUT THE VENTRICLE CELLS RECEIVING THE FASTER IMPULSES FROM THE SINOATRIAL NODE HAS TO BE FASTER TO SHORTEN THEIR DUTY CYCLE AS WELL, THAT'S WHERE THE PROBLEM LIES WITH AGING. THIS IS A SUMMARY THEN AGING EXTRACTS ORDER FROM CHAOS. WE CAN USE THESE TYPES OF WORDS TO DESCRIBE WHAT'S HAPPENING TO CARDIAC FUNCTION ON THE TYPES I WAS TELLING YOU TODAY. AND FUNCTION AND A LOT OF OTHER ORGANS. KINETICS IS IMPORTANT, MOLECULES DON'T DO THEIR JOBS AS FAST AS THEY SHOULD. MEASURING TENS OF HUNDREDS OF MILLISECONDS TIME SCALE IN THESE STUDIES. SINOATRIAL NODE DETERIORATION IS INEVITABLE. DUE TO PROGRESSIVE INTERACTION AMONG THE AGE ASSOCIATED MOLECULAR DISORDER AND GENETICS AND LIFESTYLE. WE SHOULD THROW ENVIRONMENT IN THERE. PROGRESSIVE DISORDER TRANSITION TO CLINICAL DISEASE. OUR STUDIES ARABLE LOOK AT THE STAGE WHEN THE AGING PRECEDES THE DISEASE TO SHOW WHAT'S SETTING UP HERBAL SOIL FOR THE DISEASE TO TAKE PLACE. ANIMAL MODELS RECAPITULATE ASPECT OF THE AGE ASSOCIATED SOUND STRUCTURAL FUNCTIONAL DETERIORATION, WE NEED TO STUDY THIS AS A SYSTEM, NOT AS A FUNCTION -- SINGLE FUNCTION IN ISOLATION AS HAS BEEN THE CASE IN A LOT OF PREVIOUS STUDIES. AND WE NEED TO DELAY OR INTERVENE TO PREVENT THE TRANSITION FROM THIS INEVITABLE SUBCLINICAL DETERIORATION OF SINE DIE TRIAL NODE STRUCTURE AND FUNCTION CLINICAL DISEASE. THESE ARE THE PEOPLE WHO -- INVOLVED IN THE STUDIES, YOU DON'T WANT TO MESS WITH THEM. THANKS FOR YOUR ATTENTION. [APPLAUSE] >> RAPIDLY SUM UP AND GET TO ANY QUESTIONS. DR. HOLTZMAN, >> EARLIER IN YOUR TALK YOU SHOWED EVIDENCE THE SINOATRIAL FUNCTION DEE TIER YEAR RATED WITH -- OR THE PREVALENCE WAS HIGHER IN FEMALES THAN MALES BUT IT WAS SHIFTED TO THE RIGHT. IT WAS DELAYED. >> THEY REACH PRETTY MUCH THE SAME -- ACTUALLY HEART DISEASE IS THAT WAY. IT WAS DELAYED BUT WHEN YOU GET TO OLDER AGE, THE WOMEN HAVE HIGHER INCIDENCE OR GREATER PREVALENCE. >> DO YOU THINK THAT'S SAME PHENOMENON AS HEART DISEASE? >> I THINK WE SEE IT ALL THE TIME IN A LOT OF OTHER TYPES OF EXPERIMENTS THAT I COULDN'T SHOW HERE IN A LOT OF THE DATA IN THE LITERATURE, THERE ARE SOME STUDIES THAT HAVE LOOKED AT GENDER DIFFERENCES IN THE KINDS OF MEASUREMENTS THAT I WAS MAKING HERE THE RESPONSE TO STRESS OF HEART CELLS. VENTRICULAR MONOCYTES, FEMALE CELLS DO BETTER EXPOSED TO HYPOXIA, WHY DO THEY DO BETTER? IT LIKELY HAS TO DO SOMETHING TO DO WITH SEX HORMONES AND THEY ACT BELLS AND WHISTLES WITH THESE CARTOONS THEY MODULATE THOSE AS WELL SOP CERTAIN PERIOD HAVING THOSE MECHANISMS INTACT MAKING THE FEMALE HEART STRONGER. >> I WONDER IF YOU WOULD SPEAK TO TRANSLATIONAL IMPLICATIONS OF THIS MODEL IN TERMS OF WHO YOU PREDICT IS GOING TO HAVE MORE SEVERE LESS SEVERE ONSET OF SINOATRIAL FAILURE WITH AGING IS THERE SOMETHING TO PREVENT THAT OR IS THERE PHARMACOLOGICAL -- TO REVERSE THESE PROBLEM? WHAT DOES THIS MEAN FOR PEOPLE? >> WE HAVE TO BEGIN NOT WITH PEOPLE, YOU HAVE A TRANSLATIONAL RESEARCH, WE HAVE A PATENT FOR A BIOLOGIC PACEMAKER TO EVENTUALLY REPLACE ARTIFICIAL PACEMAKERS THAT ARE IMPLANTED NOW AT SUCH A GREAT COST AND PROBLEM. WHAT WE DID SO FAR OUR IDEA WAS TO OVEREXPRESS CYCLASE 8 THAT'S THE CYCLASE DRIVING THE FUNCTION THIS IS THE HEART RATE FOR 24 HOURS IN THE TRANSGENIC AND THE WILD TYPE SO THIS WORKS IN SRI VOW THIS IS THE BASAL, ALSO YOU WOULD EXPECT THAT THE INTRINSIC HEART RATE IS HIGHER BECAUSE WE'RE GENETICALLY MANIPULATING THAT, AND IT IS. SO THIS IS DEVOID OF AUTONOMIC INPUT. THESE ARE THE PERMEABLE CELLS THE SIZE OF THE CALCIUM RELEASES THAT ARE IMPORTANT TOe1 THE CALCIUM CLOCK AND DURATION OF THEIR SIGNAL. YOU SEE THESE HISTOGRAMS DISTRIBUTIONS THAT ARE SHIFTED TO BIGGER NUMBERS IN THE AC 8 SO THIS IS PROOF OF CONCEPT THIS TYPE OF GENETIC MANIPULATION WOULD WORK FAR FROM BEING APPLIED RIGHT NOW. THIS SORT ANOTHER IDEA IS TO REPROGRAM HEART PACEMAKER CELLS BACK TO EMBRYONIC STAGE. I DON'T HAVE TIME TO SHOW YOU ALL THE DATA BUT IT HAPPENS, TBX 18 AND A COUPLE OF OTHER MARKERS THAT DETERMINE THE PACEMAKER CELL LINEAGE CAN BE MANIPULATED WITH THESE INTERVENTIONS. >> IMPAIRED CALCIUM TRANSPORT ACROSS MEMBRANE COULD BE DUE TO DAMAGE TO THE TRANSPORT WHETHER ENZYME IS TRANSPORTING ACROSS, BUT IT'S AN ENERGY DEPENDENT PROCESS, IT COULD BE DUE TO DECLINE IN MITOCHONDRIAL FUNCTION AND AVAILABILITY OF ATP TO MAKE THAT TRANSFER BOTH TO DO WITH AGING, OR DO YOU ATTRIBUTE THIS TO EITHER? >> WE HAVE DONE A GREAT DEAL OF WORK ON THE ENERGETICS OF THE PACEMAKER CELL COMPARED TO VENTRICULAR MYOSITES AND ALTHOUGH IT HAS ABOUT 10% CONTRACTILE MATERIAL WHICH USES THE ATP AND VENTRICLE CELLS IT HAS AS HIGH AS OXYGEN CONSUMPTION AS VENTRICLE CELLS, DUE TO BEING ABLE TO REGULATE THE ION GRADIANTS, WE HAVEN'T APPLIED THOSE THINGS TO AGING WE'RE WORKING ON SINGLE CELL MEASUREMENT FOR ATP AND WE LOOK AT THAT IN OUR AGING MODEL. >> THANK YOU VERY MUCH, DR. LAKATTA. THAT ENDS THE OPEN SESSION OF THE NATIONAL COUNCIL ON AGING BUT WE'RE NOT DONE YET FOLKS. THERE IS A SHORT CLOSED SESSION THAT'S GOING TO HAPPEN NOW AND FOR THE CLOSED SESSION THE ONLY PEOPLE WHO CAN BE IN THE ROOM ARE NIA STAFF DIVISION DIRECTORS AND ABOVE. AS WELL AS COUNCIL, OF COURSE.