CAPTIONS START IN A FEW MINUTES >> AND IN 2012 AS YOU CAN SEE ON THIS SLIDE, NINDS INVESTED ABOUT $155 MILLION IN PARKINSON'S RESEARCH. AND ALMOST TWO-THIRDS OF THOSE DOLLARS CAME FROM NINDS. SO WHAT DO WE FUND WITH THIS MONEY? WE FUND BASIC RESEARCH WHICH LEVERAGES RAPIDLY DEVELOPING TECHNOLOGIES THAT CONTINUE TO ADVANCE THE IDENTIFICATION OF RESEARCH GENES AND ENVIRONMENTAL FACTORS INVOLVED IN THE DEVELOPMENT OF PROGRESSION OF PARKINSON'S DISEASE. SO VERY RECENTLY THERE WAS A PAPER THAT WE HAD SUPPORTED ON RESEARCH WE SUPPORTED THAT SHOWED THAT IN THE SUBSTANTIA NIGRA THESE CELLS DEGENERATE AND GIVE RISE TO SYMPTOMS OF PARKINSON'S DISEASE THE. THAT PART OF THAT CELL DEATH OF NIGRA CELLS IS CONSEQUENCE OF A BREAKDOWN IN THE PROCESS THAT ALLOWS CELLS TO ACTUALLY DISPOSE OF DAMAGED MITOCHONDRIA. SO INVESTIGATORS SYSTEMATICALLY INHIBITD THE ACTIVITY OF OVER 20,000 GENES. ANDVATED THEIR ROLE INVESTIGATED THEIR ROLE IN THIS PROCESS AND CAME UP WITH A SERIES OF NEW PROTEINS THAT MAY REPRESENT NEW PARKINSON'S DISEASE THERAPEUTIC TARGETS. ANOTHER EXAMPLE OF A SIGNIFICANT BASIC SCIENCE FINDING IS THAT WE ALL KNOW LOUIS BODIES AGGREGATION OF PROTEINS IN THE CELLS AND PARTNERS WITH PARKINSON'S DISEASE CONTAIN ALPHA SYNUCLEIN, A TOXIC PROTEIN AND SCIENTISTS WITH NIH FUNDING HAVE SHOWN THAT THE SYNUCLEIN FIBRILS CAN MOVE FROM NEURON TO NEURON AND THIS PROVIDES AN INTERESTING EXPLANATION OF WHY CELL DEATH SPREADS AND PROVIDES A TARGET. WE SUPPORT TRANSLATIONAL RESEARCH. WE HAVE IN A REPOSITORY A WHOLE SERIES OF INDUCED PLURIPOTENT STEM CELLS FROM PATIENTS WITH INHERENT FORMS OF PARKINSON'S DISEASE, THESE ARE AVAILABLE TO THE PUBLIC TO SCIENTISTS TO BE USED TO LOOK AT PATHOGENESIS AND ALSO TO LOOK AT POTENTIAL TREATMENTS. WE HAVE INITIATED CRITICAL EFFORTS TO ACCELERATE THE SEARCH FOR BIOMARKERS. THESE ARE CHANGES IN THE BODY THAT CAN ACTUALLY BE USED TO PREDICT DIAGNOSE OR MONITOR DISEASE. AND CAN SERVE MOST IMPORTANTLY AS A WAY TO INCREASE THE SPEED AT WHICH WE CAN RUN CLINICAL TRIALS. THIS YEAR WE LAUNCHED THE PARKINSON'S DISEASE BIOMARKERS PROJECT TO FOSTER BIOMARKER DISCOVERY. THIS PROJECT ACTUALLY IS VERY COMPLIMENTARY TO THE MICHAEL J. FOX PROJECT. PPMI, PARKINSON'S PROGRESSION MARKER INITIATIVE WHICH WILL PURSUE BIOMARKER VALIDATION. WE ALSO IN OUR FIRST ACTIVE COLLABORATION WITH MICHAEL J. FOX FOUNDATION HAVE STARTED THE BIOFINE PROJECT WHICH IS LOOKING AT A CROSS SECTION OF PARKINSON'S PATIENTS AND COLLECTING SAMPLES THAT WILL BE AVAILABLE TO INVESTIGATORS TO STUDY. FINALLY WE STUDY -- WE HAVE A VERY ROBUST CLINICAL TRIALS PROGRAM,. ONE THING AT THE NINDS IS PUT TOGETHER A SET OF ATTRIBUTES, COMMON DATA ELEMENTS FOR PARKINSON'S DISEASE WE ARE ASKING ALL PEOPLE WHO DO CLINICAL STUDIES INCLUDING CLINICAL TRIALS TO USE AND WHAT THIS WILL DO IS WILL STANDARDIZE THE COLLECTION OF DATA IN OUR CLINICAL STUDIES AND TRIALS AND ALLOW A BETTER COMPARISON ACROSS TRIALS AND ENHANCE THE SPEED WHICH WE CAN MAKE PROGRESS. CLINICAL TRIALS WE FUNDED WITH THE VETERAN ADMINISTRATION SHOWN DEEP BRAIN STIMULATION IS MORE EFFECTIVE AS BEST TREATMENT FOR PARKINSON'S AND THE BENEFICIAL EFFECTS OF DBS LAST FOR 36 MONTHS. WE HAVE ALSO -- THIS IS NOT SO POSITIVE IN SOME WAYS BUT POSITIVE IN OTHERS HAVE RUN CLINICAL TRIALS TO SHOWY TREATMENTS ARE NOT EFFECTIVE. FOR EXAMPLE, A RECENT TRIAL THAT LOOKED AT WHETHER CREATINE SLOWS PROGRESSION OF PARKINSON'S DISEASE WAS CLOSED EARLY LIKE THE TRIAL ON COQ 10. HOW DO WE FUND RESEARCH? WE FUND TEN ADOLL OF CENTERS, CENTERS OF EXCELLENCE IN PARKINSON'S DISEASE AND THEY COVER A WIDE RANGE OF TOPICS. WE ALSO FUND INVESTIGATOR INITIATED RESEARCH AND THIS IS RESEARCH PROPOSED BY INVESTIGATORS WHO ARE SCANNING RESEARCH LANDSCAPE WITH PROMISING OPPORTUNITIES. WE ARE SPECIAL INITIATIVES. WE SUPPORT RESEARCH ON RESOURCES THAT ARE IMPORTANT FOR PARKINSON'S DISEASE RESEARCH COMMUNITY. SOME EXAMPLES OF THIS ARE THE REPOSITORY WHICH HAS DNA SAMPLES USED FOR PARKINSON'S GENETICS AND THAT HOUSES FIBROBLASTS AND INDUCED PLURIPOTENT STEM CELLS L FOR PARKINSON'S. THE MOST RECENT ADDITION TO THIS RESOURCE SET IS NEW NEUROBIOBANK RECENTLY ANNOUNCED AND THIS IS GOING TO BE A COLLECTION OF BRAIN BANKS FUNDED BY NINDS, NIH AND CHILD HUMAN HEALTH DEVELOPMENT INSTITUTE AND WHAT IS UNUSUAL ABOUT THIS IS THE INFORMATION ABOUT ALL THOSE SAMPLES THAT -- BRAIN SAMPLES AVAILABLE FOR PEOPLE TO STUDY, ARE LISTED IN A DATABASE AND WILL BE MUCH MORE AVAILABLE BECAUSE OF THIS THAN THEY HAVE BEEN BEFORE. I WANT TO SAY A FEW WORDS ABOUT THE MOST RECENT FEDERAL INITIATIVE RELATED TO BRAIN RESEARCH. THIS IS THE NEW RESEARCH PRESIDENT OBAMA ANNOUNCED NOVEMBER 2ND, ADVANCING INNOVATIVE TECHNOLOGIES. THIS WAS INCREDIBLY EXCITING FOR THE NEUROSCIENCE COMMUNITY RESEARCHERS, PATIENTS, PATIENT ADVOCATES, BECAUSE IT IDENTIFIED AT THE HIGHEST LEVEL AND FEDERAL GOVERNMENT BRAIN RESEARCH AS EXTREMELY IMPORTANT PRIORITY. THE GOAL IS TO ACTUALLY ACCELERATE DEVELOPMENT APPLICATION, INNOVATIVE TECHNOLOGIES CONSTRUCT A DYNAMIC PICTURE OF BRAIN FUNCTION OVER TIME. AND THIS HAS HUGE IMPACT NOT ONLY BASIC SCIENCE UNDERSTANDING BRAIN FUNCTION BUT FOR MANY, MANY DIFFERENT DISEASES. THE FIRST INITIATIVE FIRST ROUND OF FUNDING OPPORTUNITIES THAT SUPPORTED THE PRESIDENT'S BRAIN INITIATIVE WERE RELEASED ON DECEMBER 16th SO THOSE IN THE RESEARCH COMMUNITY, LOOK AT THE INITIATIVES TO SEE IF THERE ARE OPPORTUNITIES FOR YOU THERE. SO THE GOALS OF THE MEETING ARE TO TAKE ADVANTAGE OF ALL THE PLANNING THAT'S BEEN GOING ON FOR THE PAST SEVERAL MONTHS TO COME UP WITH A SET OF RECOMMENDATIONS FOR WHERE THE FIELD SHOULD GO. WHAT WE HAVE DONE -- NOT WHAT WE, WHAT THE WHOLE COMMUNITY HAS DONE IS TO ACTUALLY LOOK AT ADVANCES THE PAST EIGHT YEARS AND TRY TO SYNTHESIZE INTO A REASONABLE NUMBER OF RECOMMENDATIONS SO WHAT WE WILL BE DOING AT THIS MEETING IS LOOK THROUGH THE RECOMMENDATIONS AND PRIORITIZE THEM AND MAKE SURE WE HAVE THE FULL COMPLIMENT OF ACTIVITIES. SO WE LOOK FORWARD TO FEEDBACK ON THE PREVENTIVE RESEARCH RECOMMENDATIONS FOR ALL MEETING PARTICIPANTS. SIGNS RESEARCHERS AND MEMBERS OF THE LAY IMMUNITY INCLUDING PEOPLE WITH PARKINSON'S, FAMILY MEMBERS AN CAREGIVERS. WHILE THESE RECOMMENDATIONS ARE SPECIFICALLY TO INFORM NINDS ON ITS EFFORTS IN PARKINSON'S DISEASE RESEARCH, WE REALIZE THAT THIS SET OF RECOMMENDATIONS HAVE IMPACT -- HAVE VALUE FOR OTHER PARTNERING FOUNDATIONS, ORGANIZATIONS OTHER NIH INSTITUTES AND FEDERAL AGENCIES AS WELL AS NON-PROFIT AND ADVOCACY COMMUNITIES. SO IN MANY WAYS THE PLANNING HAS BEEN GOING ON FOR SOME TIME. THIS IS A POINT WHICH THE START OF A CONVERSATION AMONG PARKINSON'S DISEASE FUNDING ENTITIES AND ADVOCACY ORGANIZATIONS AND IT'S OUR HOPE THIS CONTINUED CONVERSATION WILL FACILITATE REACHING OUR COMMON GOAL OF REDUCING THE BURDEN OF PARKINSON'S DISEASE. TOWARD THAT END WE'RE BEGINNING TO TALK TO THE MICHAEL J. FOX FOUNDATION, HAVING A JOINT DISCUSSION. HOW WE TOGETHER WITH OTHER ORGANIZATIONS CAN TALK ABOUT ACHIEVING THESE GOALS. AND PLANNING A MEETING WITH NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES TO EXPLORE THE ENVIRONMENTAL CAUSES AND IMPACT OF ENVIRONMENTAL FACTORS ON PARKINSON'S DISEASE THAT IS ABSENT, FOR THE MOST PART FOR THIS SET OF RECOMMENDATIONS BUT WE LOOK FORWARD TO ACTUALLY ADDRESSING THAT. SO THANK YOU. THIS IS -- HAS BEEN AN EFFORT BY A HUGE COLLECTION OF PEOPLE, WE HAVE BEEN FORTUNATE TO HAVE AQUEDUCTED GROUP OF SESSION CHAIRS WHOSE NAMES ARE IN BOLD. UNFORTUNATELY BECAUSE OF WEATHER A NUMBER OF PEOPLE WILL NOT GET TO FLY INTO D.C. BECAUSE THEY CAN'T GET OUT OF AIRPORTS IN THE MIDWEST. MANY, MANY PANEL MEMBERS AGAIN, SOME WHOM WILL NOT GET TOO COME. THESE PEOPLE WORKED OVER MONTHS TIRELESSLY TO HELP COME UP WITH RECOMMENDATIONS TO PRIORITIZE THEM TO WORK BETWEEN GROUPS. IN ADDITION TO PEOPLE OUTSIDE THE NIH, THERE ARE A NUMBER OF NINDS STAFF WHO WORKED EXTREMELY HARD ON THIS, MARY EM MER FROM COMMUNICATIONS, GAL PERT, WALTER CORE SHITS, MARTHA AND BETH AND SEE BEAR. MARGARET SUTHERLAND AND HAO WEIGH AND WE ARE GRATEFUL TO THEM. SO SO THE GOALS ARE OUTLINED. I DO WANT TO THANK THE IMPORTANT COLLABORATORS IN OUR COMMON EFFORT. PARKINSON'S ACTION NET WORK. I SAW AMY RICK COME IN AND MICHAEL J. FOX FOUNDATION, PARKINSON'S DISEASE FOUNDATION, NATIONAL PARKINSON'S FOUNDATION AND PARKINSON'S ALLIANCE. WE WILL BE WORKING TOGETHER. I KNOW THE RECOMMENDATIONS FROM THIS MEETING WILL BE A KEY PART OF THE UPCOMING PARKINSON'S ACTION NETWORK MEETING IN D. C. CXFC PARKINSON'S ACTION NETWORK PARTICIPANTS H TAKE THESE RECOMMENDATIONS TO CONGRESS PEOPLE ON THE HILL. EVERYONE WHO IS HERE AND EVERYONE WHO IS WATCHING THIS ON VIDEO, I WANT TO THANK YOU ALL FOR PARTICIPATING IN TODAY'S CONFERENCE. WITH YOUR INPUT WE WILL REACH A CONSENSUS. ONE OF THE QUESTIONS THAT I HAVE HEARD REPEATEDLY ABOUT THIS MEETING AND I KNOW MEMBERS ON THE PLANNING PANEL HAVE ASKED AND NINDS STAFF HAVE HEARD IS WHAT HAPPENS TO THESE RECOMMENDATIONS? WILL THEY ACTUALLY MAKE A DIFFERENCE? WILL NIH ACT ON THEM? OR WILL THEY BE PUT ON THE SHELF? THAT'S THE QUESTION. I HAVE TO SAY WHEN WE STARTED THE PLANNING FOR THIS MEETING IN EARNEST RIGHT AFTER THE SHUTDOWN, Y'ALL REMEMBER THE SHUTDOWN? WE WERE FACING CONTINUATION OF THE 5% SEQUESTER CUTS. IN OUR BUDGETS LIKE OTHER DISCRETIONARY FUNDING. WE WERE LOOKING FORWARD -- NOT SURE THAT'S THE RIGHT PHRASE, ADDITIONAL 2% CUT. EVEN THOUGH WE DON'T KNOW WHAT OUR FINAL BUDGET WILL BE RECENT ACTIONS OF CONGRESS MAKE IT VERY CLEAR THAT THE IMPORTANCE OF WHAT NIH DOES, WHAT NINDS DOES AND OUR MISSION TO REDUCE THE BURDEN OF DISEASE ACROSS ALL DISORDERS HAS BEEN RECOGNIZED. I NOW AM MUCH MORE SANE THAT SOME OF THE CUTS THAT WERE TAKEN FROM THE SEQUESTER WILL ACTUALLY BE RESTORED AND THAT WILL MAKE A HUGE DIFFERENCE HOW WE CAN IMPLEMENT THESE RECOMMENDATIONSES. I'M GOING TO TURN THE MICROPHONE OVER TO TOM MONTINE, DISTINGUISHED CHAIR WHO HAS CONDITION AN EXTRAORDINARY AMOUNT OF WORK INNED TODAY'S IN -- I WANT TO APOLOGIZE, I'M GOING TO HAVE TO LEAVE TO GO TO A MEETING OF THE IC DIRECTORS, NEW FUNDING MECHANISMS THAT GIVE STABILITY TO ESTABLISH INVESTIGATORS HOW TO FUND EARLY STAGE INVESTIGATORS, SHOULD WE REORGANIZE REVIEW ONCE AGAIN SHOULD WE HAVE BETTER MECHANISMS TO COORDINATE AND OTHER ISSUES WHICH WHILE PROBABLY NOT SCIENTIFICALLY INTERESTING AS THIS PARKINSON'S CONFERENCE WILL HAVE A BIG IMPACT HOW Y'ALL CONDUCT RESEARCH AND OUR ABILITY TO MOVE THE AGENDA OF THIS CONFERENCE FORWARD. SO THANK YOU VERY MUCH AND SEE YOU TOMORROW MORNING. I'LL SEE YOU WITH THE PANEL THIS AFTERNOON. [APPLAUSE] >> GOOD MORNING, EVERYONE. THANK YOU, STORY. THANK YOU, EVERYONE, FOR JOINING US. MY NAME IS TODD MONTINE, PROFESSOR AT THE UNIVERSITY OF WASHINGTON, I HAVE THE PRIVILEGE OF BEING SCIENTIFIC CHAIR FOR TODAY AND TOMORROW'S MEETING. DR. ANN SIEBER. DR. CHRISTINE TORBERG. OUTSTANDINGVINGS AND STAFF HERE AT THE HUNDRED DOLLARS THAT STORY OUTLINE -- NINDS THAT STORY OUTLINE. WE'RE CHARGED WITH LEADING AN EFFORT TO HAVE THE GOAL OF PRODUCING PRIORITIZED RESEARCH RECOMMENDATIONS FOR PARKINSON'S DISEASE. THIS CONFERENCE IS ONE COMPONENT OF SEVERAL COMPONENTS IN THAT EFFORT SUCH AS TO REVIEW FOR YOU WHERE WE ARE IN THIS STREAM. WE BEGAN LAST SUMMER, WE WERE STORY SAID DELAYED SOMEWHAT IN THE FALL. BUT WE STARTED LAST SUMMER AND OUR FIRST WAS TO ORGANIZE OURSELVES INTO GROUPS AND DIVIDE THE WORK INTO THREE AREAS. CLINICAL RESEARCH TRANSLATIONAL RESEARCH AND BASIC RESEARCH. WE THEN SELECTED OOH PANEL OF EXPERTS TO DEVELOP DRAFT PRIORITIZED RECOMMENDATIONS AND I UNDERSCORE THE WORD DRAFT. THOSE DRAFT RECOMMENDATIONS ARE NOW IN FRONT OF YOU. SO THAT'S THE PRODUCT OF WORK OVER THE LAST SEVERAL MONTHS. THAT BRINGS US LITERALLY INTO YESTERDAY. AND NOW TODAY AND TOMORROW'S CONFERENCE. I'LL COME BACK TO THE PURPOSE OF THE CONFERENCE IN A MOMENT. WHAT WE HAVE DONE HERE THE NEXT STEP IS REVISE THE DRAFT TO MAKE THE FINAL RECOMMENDATION THAT WILL BE PUT INTO A REPORT AND PRESENTED TO HUNDRED DOLLARS COUNCIL AT THE END OF THIS MONTH. THAT TIME LINE IS IMPORTANT TO INTERFACE WITH PARKINSON'S ACTION NETWORK AND EFFORTS ON CAPITOL HILL. SO WHY THIS CONFERENCE? OUR GOAL IS TO DEVELOP PRIORITIZED RESEARCH RECOMMENDATIONS FOR PARKINSON'S DISEASE. THIS IS ONE OF SEVERAL STEPS WE NEED TO TAKE. THE PURPOSE TODAY IS TO OBTAIN YOUR INPUT ON THE CONTENT AND RANKING OF THOSE RECOMMENDATIONS. SO IF I COULD, I THINK THE PROPER WAY TO LOOK AT THIS WE CONVENED PAMS TO WORK OVER THE LAST -- PANELS TO WORK OVER THE LAST FEW MONTHS OF A MANAGEABLE SIZE OF EXPERTS. VERY DIFFICULT TO PULL PEOPLE TOGETHER FROM AROUND THE GLOBE TO THE PARTICIPATE IN THESE COMMITTEES. THAT'S PHASE 1. PHASE 2 IS WHAT WE DO HERE TODAY AND TOMORROW. THIS IS NOT THE USUAL SCIENTIFIC SYMPOSIUM, WE VIEW EVERYONE HERE EVERYONE JOINING US ONLINE AS THE NEXT PANEL OF EXPERTS. OUR GOAL IS TO GET YOUR INPUTS. OUR EXPERTISE VARIES. THOSE THAT ARE HERE, SOME OF US ARE EXPERTS FROM COPING WITH THIS DISEASE EVERY DAY. SOME FROM CARING FOR LOVED ONES WHO HAD OR HAVE HAD PARKINSON'S DISEASE. SOME OF US EXPERTS AS ADVOCATES FOR THOSE WITH PARKINSON'S DISEASE OR HEALTHCARE PROVIDERS. MANY OF US HERE AS PHYSICIANS OR SCIENTISTS IN GOVERNMENT INDUSTRY OR UNIVERSITY AND LOTS OF US HAVE MULTIPLE ROLES. THIS PHASE 1 AS I SAID, THIS DRAFTING PHASE IS NOW DONE. THOSE OF US ON THE PANELS ARE PAINFULLY AWARE OF WHAT OUR OTHER PANEL MEMBERS THINK. SO WE DON'T NEED TO DO THAT, WE IMMEDIATE YOUR INPUT OF EVERYONE HERE AND ONLINE. THERE WILL BE SEVERAL WAY, GET TO THAT IN A MOMENT, SO Z I ASK YOUR INPUT TO PROVOKE YOU TO OUR RECOMMENDATIONS I ALSO NEED TO ASK YOU TO PLEASE REMEMBER TO STAY FOCUSED ON OUR GOAL. THE GOAL OF TODAY AND TOMORROW TO DEVELOP PRIORITIZED RESEARCH RECOMMENDATIONS. MY JOB IS TO KEEP US ON TASK AND ON TIME. SO I ASK YOUR INDULGENCE. PLEASE UNDERSTAND IF I OR ONE OF MY COLLEAGUES GUIDE THE DISCUSSION OR ASK WE HOLD OFF, AN ITEM HAS BEEN DISCUSSED AT LENGTH OR IF WE KNOW IT WILL BE COMING UP IN A SESSION LATER IN THE CONFERENCE. TIME IS TIGHT AND WE'LL TRY OUR BEST TO PROMOTE INPUT BUT GUIDE SO WE STAY ON TIME AND TASK. THERE ARE FOUR FORMATS. FIRST FOR OUR PANEL DEVELOPED THE DRAFT RECOMMENDATIONS TO PRESENT THE RATIONALE SO WE ARE UP TO SPEED WHERE WE ARE. EACH SCIENTIFIC PRESENTATION IS FOLLOWED BY A DISCUSSION SECTION WHERE YOU CAN HAVE INPUT IF YOU PREFER TO WRITE YOUR QUESTION DOWN AND THOSE JOINING US ONLINE CAN SEND YOUR QUESTIONS IN BY EMAIL. I ASK YOU TO CONCENTRATE ON TWO THINGS. WE NEED YOUR THOUGHTS ABOUT THOSE YOU THINK SHOULDN'T BE ON THE LEST AND THOSE WHO SHOULDN'T BE ON THE LIST, THOSE ARE QUESTIONS TO KEEP IN MIND AS FAR AS CONTENT. THE OTHER KEY ISSUE IS RANKING. IS THE SECOND IS FORUM FOR ADVOCACY EXPERTS WE'LL HAVE THIS AFTERNOON. THE THIRD IS PUBLIC COMMENT SESSION WE'LL HAVE TOMORROW AFTERNOON. THANK YOU TO EVERYONE HERE ONLINE WHO HAVE ALREADY SENT IN THEIR QUESTIONS AND COMMENTS FOR THE PUBLIC SESSION. FINALLY, WE'LL HAVE SUMMARY SESSION AS OUR LAST EVENTS WHERE WE WILL REVIEW EVERY SUGGESTION AND COMMENT MADE BY YOU OUR EXPANDED PANEL OF EXPERTS TO BE SURE WE HAVE -- IF NOT WILL TRY THE REACH CONSENSUS, IF WE CAN'T WE'LL RECOGNIZE EVERY OPINION ADVANCED. THE SUCCESS IN OUR EFFORT DEPENDS IMPORTANTLY ON THIS CONFERENCE AND SUCCESS OF THIS CONFERENCE DEPENDS ENTIRELY ON YOU. SO PLEASE DON'T BE BASHFUL. PUT FORWARD YOUR EXPERT OPINION AS WE MOVE THROUGH SCIENTIFIC SESSIONS AND OUR OPEN SESSIONS. SO THANK YOU AGAIN VERY MUCH FOR JOINING US. THANK YOU TO EVERYONE WHO WORKED VERY HARD TO BRING US TO THIS POINT. WE'LL START WITH THE FIRST SESSION WILL BE ON CLINICAL RESEARCH AND LEADERS OF THAT GROUP ARE DR. ANDY BATHEMAN FROM WASHINGTON UNIVERSITY, AND DREW SIDEROWF FROM AVID RADIO PHARMACEUTICALS. WENDY HALPERN AND DR. KOROSHETZ FROM NINDS. I BELIEVE I'LL BE HANDING THE PODIUM TO ANDY. SO THANK YOU, EVERYONE FOR JOINING US AND LET'S HAVE AN ACTIVE CONFERENCE. ANDY. >> GOOD MORNING, EVERYONE. I'M ANDREW SIDEROWF FROM AVID RADIO PHARMACEUTICALS IN PHILADELPHIA. IT'S A PLEASURE TO BE HERE TODAY TO REPRESENT THE CLINICAL WORKING GROUP FOR THIS MEETING. I WANT TO ACKNOWLEDGE RANDY BATHEMAN, ONE OF THE -- BATEMAN WHO IS ONE OF THE PEOPLE THAT GOT STUCK IN THE MIDWEST AS MY CO-CHAIR AND ALSO THANK WENDY GALPERN AND WALLER KOROSHETZ WHO WORKED SINCE THE END OF FALL TO GET THE CLINICAL RECOMMENDATIONS IN SHAPE. I ALSO WANT TO THANK TOM UPON TINE, LASER LIKE FOCUS -- MONTINE, WHOSE LASER GOALS KEPT US ON TRACK. DR. BETH SIEBER AT THE NINDS WHO HAS THE LOGISTICS FOR OUR GROUP OVER THE LAST FEW DAYS. AND SO I WANT TO START OUT WITH THIS SLIDE, I WANT TO MAKE A COUPLE OF POINTS. FOR THOSE TAKING CARE OF PARKINSON'S PATIENTS, EASY TO GET PETS MISTIC AT TIMES. REALLY THE -- PESSIMISTIC AT TIMES. OPTIMISM SHOULD BE THE WATCH WORD OF THE DAY BECAUSE THERE'S BEEN DRAMATIC CONTRIBUTIONS FROM CLINICAL RESERGE THAT MAKE A DIFFERENCE IN LIVES OF PARKINSON'S PATIENTS FROM THE DEVELOPMENT OF BIOMARKERS LIKE DOPAMINERGIC IMAGING WHICH IS A THING MY COMPANY WORKS ON, GENETICS, AND IMPORTANTLY BOTTOM TWO PANELS OF THIS SLIDE, TREATMENTS THAT HAVE A REAL EFFECT ON THE LIVES OF PATIENTS WITH PARKINSON'S DISEASE INCLUDING MEDICAL THERAPIES LIKE LEVODOPA SHOWN THERE, THIS IS THE ELDOPA TRIAL, NINDS SPONSORED STUDY SHOWING THE OBVIOUS WELL KNOWN EFFECTS OF LEVADOPA, DISABILITY AND PARKINSON'S DISEASE, AND SURGICAL THERAPIES LIKE DBS, THIS BOTTOM PANEL IS ONE OF PHIL STARR, MEMBER OUR PANEL'S PATIENTS AND ANYBODY WHO IS TAKING CARE OF DBS PATIENT WHO HAD DBS OR A PATIENT WITH DBS KNOWS OF A LIFE CHANGING BENEFIT THAT DBS CAN HAVE FOR WELL SELECTED PARKINSON'S PATIENTS. SO MAJOR CONTRIBUTIONS AND SUCCESSES IN THE PAST, THIS IS A FOUNDATION FOR OPTIMISM. THE OTHER KEY POINT I WANT TO MAKE IS THESE CONTRIBUTIONS THE BEST COME FROM A COLLABORATION BETWEEN CLINICAL SCIENTISTS AND BASIC SCIENTISTS. THINK ABOUT DBS, INSIGHTS CAME FROM ANIMAL LABORATORIES THAT LED TO THE DEVELOPMENT OF THIS THERAPY FOR PATIENTS WITH PARKINSON'S DISEASE. LIKEWISE WITH GENETICS, THE MAYBE INSIGHT CAME FROM LABORATORIES, GENETICS LABORATORIES AND TECHNOLOGY. BUT EACH OF THE CIRCLES AND SQUARES ON THAT FAMILY TREE REPRESENTS A PATIENT WITH PARKINSON'S OR FAMILY MEMBER OF A PATIENT WITH PARKINSON'S. THE CLINICS PROVIDE THE MATERIAL THE GENETICISTS WORK ON TO MAKE DISCOVERIES SO THESE DISCOVERIES REQUIRE VERTICAL INTEGRATION BETWEEN THE BENCH SCIENTISTS AND CLINICAL SCIENTISTS TO DELIVER LIFE-CHANGING THERAPIES AN INSIGHTS TO PATIENTS WITH PARKINSON'S DISEASE. THE SECOND POINT TO MAKE INTRODUCING OUR SESSION IS GO OVER THE PROCESS A LITTLE BIT. WE HAD A GREAT GROUP. YOU CAN SEE THEM LISTED THERE TO YOUR LEFT. EXPERTISE FROM BIOSTATISTICS REGULATORY TRIAL DESIGN, CLINICAL MEASUREMENT. A LOT YOU WON'T SEE BECAUSE THEY GOT STUCK IN TRAVEL, WE HAVE A NUMBER OF OTHERS WHO YOU WILL HEAR ON PHONE. OUR PROCESS. WE DIVIDE INTO SUBGROUPS AN CREATE OVER 20 DIFFERENT RECOMMENDATIONS, BROUGHT THESE BACK TO THE WHOLE GROUP WHERE THEY WERE RANKED IN ORDER AND TOP 12 WERE IDENTIFIED. WE REDISCUSSED THE TOP 12 PLUS ADDITIONAL ON THE BORDERLINE AND RERANKED THEM. IN ORDER SO WHAT YOU'LL SEE TODAY IS A MODIFIED CONSENSUS PROCESS BY THE PEOPLE IN THIS GROUP. AS ONE PERSON IN OUR GROUP POINTED OUT, WE HAVE BROAD RANGE OF EXPERTISE. THESE REPRESENT THE FIELD WELL, THESE ARE OUR RECOMMENDATIONS AND WOULDN'T NECESSARILY BE EVERY PARKINSON'S EXPERT IN THE IMMUNITY. NONETHELESS WE FEEL THESE CAPTURE THE CORE THEMES THE CLINICAL L RESEARCH COMMUNITY IS FOCUSED ON. SO LAST POINT I WANT TO MAKE BEFORE I SHOW RECOMMENDATION IS JUST TO ORIENT YOU A LITTLE BIT. I THINK I KNOW WARNER IS GOING TO SHOW A SLIDE LIKE THIS AND CAR LEE WILL DURING OUR TALK TO ORIENT OURSELVES THE WAY WE THINK ANT THE NATURAL HISTORY OF PARKINSON'S DISEASE AND WHERE OUR RECOMMENDATIONS MIGHT FIT IN. I THINK THERE'S A LOT OF INTEREST TREATING CLINICAL FEATURES OF PARKINSON'S, THOSE ARE TO THE RIGHT OF TIME OF DIAGNOSIS, CLINICAL FEATURES LEVADOPA REFRACTORY MOTOR FEATURES AND NON-MOTOR FEATURES LIKE AUTONO, MA'AMIC DISTURBANCE AND SO YOU HE WILL SEE RECOMMENDATIONS THAT TARGET THOSE AREAS. THE OTHER AREA INTERESTING TO OUR GROUP WAS THE IDEA THERE WAS A LONG PRE-CLINICAL OR PRODROMAL PHASE TO PARKINSON'S MOST OPPORTUNE TO INTERVENE WITH DISEASE MODIFYING THERAPIES SO YOU'LL SEE THAT PRODROMAL PARKINSON'S DISEASE AND PRE-CLINICAL DETECTION. THE OTHER RECOMMENDATIONS YOU'LL SEE, I WILL SHOW YOU NOW, HAVE TRIAL DESIGN AND OUTCOME MEASURES SO THESE ARE OUR RECOMMENDATIONS THAT YOU'LL SEE DISCUSSED THE NEXT APPROXIMATELY THREE HOURS GROUPED INTO CATEGORIES SYMPTOMATIC TREATMENT FOR NON-MOTOR FEATURES. LEVADOPA MOTOR FEATURES AND FLUCTUATIONINGS AND DYSKINESIAS, BETTER TRIAL DESIGN INCLUDING BIOMARKERS ESPECIALLY. OUTCOME MEASURES INCLUDING USING NEW TECHNOLOGIES TO IMPROVE OUTCOME MEASURES AND ALSO INCREASE MINORITY RECRUITMENT IN RESEARCH. LASTLY, THIS IS GOING TO BE THE AREA PARTICULARLY INTERESTING TO US IS TACKING THE PROBLEM OF DISEASE STAND POINT INCLUDING PRODROMAL PD AND MANIFEST ESTABLISH CLINICAL PD. THOSE ARE THE BROAD LANDSCAPE OVER THE NEXT THREE HOURS B AND TO GET STARTED I WOULD LIKE TO INTRODUCE WERNER POEWE FROM UNDERSTAND BROOK WHO MADE THE JOURNEY ACROSS THE ATLANTIC TO BE HERE TODAY. WERNER. >> GOOD MORNING, EVERYBODY. THANK YOU ANDY AND RANDALL OF COURSE AN WENDY AND WALL WALTER FOR INVITING ME TO BE PART OF THIS EXCITING ACTIVITY TODAY. REALLY GRATEFUL AND PROUD TO BE HERE. SESSIONING OR SUBGROUP I'M REPORTING FOR SPENT SOME TIME THINKING ABOUT OPPORTUNITIES TO ADVANCE THE SYMPTOMATIC TREATMENT AUTONOMIC FEATURES OF PARKINSON'S DISEASE. AND WOULD LIKE TO COME BACK TO EVOLUTION OF PARKINSON'S DISEASE THAT ANDY ALLUDED TO NOW. AND IN TERMS OF TREATMENT AND OPPORTUNITIES FOR AND CHALLENGES FOR TREATMENT SYMPTOMATIC TREATMENT, WE HAVE DONE WELL AS YOU KNOW, WHEN IT COMES TO TREATING EARLY PARKINSON'S DISEASE WHEN DIAGNOSIS IS MADE AND MOTOR SYMPTOMS OF THE CLASSICAL SIGNS PREVAIL. LEVADOPA IS THE GOLD STANDARD HERE BUT WE RUN INTO PROBLEMS AS PARKINSON'S DISEASE ADVANCES AND WE HAVE SIGNIFICANT NUMBER OF UNMET NEEDS IN THAT ARENA. WE HAVE A WHOLE NEW ARENA OPENING UP WHICH WE ARE ADDRESS LATER TODAY WHEN IT COMES TO SOMETHING B ABOUT PREVENTING THE DISEASE BEFORE THESE MULTI-SYMPTOMS HAVE EVOLVED. OUR GROUP WAS FOCUSING ON THESE PROBLEMS OF SYMPTOMS THAT BECOME MORE PREVALENT ADVANCING PD INCLUDING MOTOR COMPLICATIONS FROM CROPPIC LEVADO FIRST QUARTERA EXPOSURE, SYMPTOMS RESISTANT TO DOPAMINERGIC SYMPTOMS LIKE LEVADOPA, THE INCREASING SPECTRUM OF NON-MOTOR PROBLEMS TO REMIND Y'ALL ABOUT THE MOTOR COMPLICATION RATES WE SEE WITH CHRONIC LEVADOPA IN PARKINSON'S. THEY'RE FREQUENT AND AFFECT HALF OF OUR PATIENTS WITH PROLONGD EXPOSURE. BUT NOT ONLY THERE AFTER MANY YEARS OF TREATMENT THEY BEGIN TO EVOLVE FROM RECENT TRIALS DEPENDING ON DOSE OF LEVADOPA, THE STUDY MADE US AWARE UP TO 60% OF PATIENTS ON HIGH DOSE LEVADOPA LED TO DISKINESIS AFTER NINE MONTHS. WE KNOW A LITTLE BIT ABOUT RISK FOR DEVELOPING THESE PROBLEMS. INCLUDING AGE, ONE OF THE MAJOR RISK FACTORS. LEVADOPA DOSE AND TREATMENT DURATION. WE CAN DO A LITTLE BIT ABOUT THEM CURRENTLY, THERE ARE TREATMENTS REVIEWED BY TASK FORCE OF INTERNATIONAL PD AND MOTOR SOCIETY AND DRUGS AND NON-DRUG SURGICAL TREATMENTS AVAILABLE RIGHT HERE, WE HAVE CERTAIN ARMAMENTARIUM OF FLUCTUATIONS ONCE DEVELOPED TO SOME EXTENT WE WILL NEVER BE ABLE TO AT PRESENT ERADICATE THEM. WE ONLY HAVE A SINGLE DRUG TO DATE TO TREAT DYSKINESIA. THAT'S AN AREA OF NEED. THAT WE ARE FACING. WHEN DISCUSSING WHERE WE HAVE KNOWLEDGE GAPS IN THE GROUP AS RELATES TO MOTOR COMPLICATIONS IN THEIR TREATMENT, IT IS NOT FORGOTTEN. NOT EVERYBODY WITH PARKINSON'S DISEASE EXPOSED TO LEVADOPA SUFFER FROM THESE PROBLEMS AND DEVELOP THEM AND WE NEED TO IDENTIFY DETERMINANTS AND MARKERS FOR THOSE AT PARTICULAR RISK BEYOND THE ESTABLISHD RISK FACTORS WE KNOW LIKE AGE. WE HAVE AN INCOMPLETE UNDERSTANDING WHAT LEADS TO DEVELOPMENT OF THESE FLUCTUATIONS IN RESPONSE DYSKINESIA AND OTHERS IN THE BRAIN AS WE EXPOSE PATIENTS TO LEVADOPA TO MAKE THEM RESPOND IN DOSES OF DRUGS THAT NEEDS TO BE HELPFUL AND BENEFICIAL WITHOUT ANY PROBLEMS EARLY IN THE DISEASE. SO WE NEED TO UNDERSTAND THE OCCURS AND WHICH SYSTEMS THAT INVOLVES AND WE NEED TO UNDERSTAND WHY THERE IS THIS AGE RISK FOR YOUNGER PATIENTS TO BE PARTICULARLY VULNERABLE AND IT ALSO SEEMS FOR FEMALES TO BE MORE VULNERABLE THAN MALES TO DEVELOPING THESE PROBLEMS. THEY INVOLVE NON-DOPAMINERGIC MECHANISMS WE HAVEN'T FULLY ELUCIDATED YET AND WE HAVE EVIDENCE POINTING OUT THERE IS AN ISSUE ABOUT CONTINUITY OF DOPAMINERGIC DRUGRY IN DEVELOPMENT OF THESE PROBLEMS AND THERE'S AREAS OF FUTURE RESEARCH WE FELT COULD ADDRESS THESE UNKNOWNS WHICH WE LAY TO IDENTIFY GENETIC AND OTHER RISK FACTORS TO USE IMAGING NEUROPHYSIOLOGY TO BETTER UNDERSTAND THE NETWORKS THAT GO WRONG. WHEN PATIENTS DEVELOP DYSKINESIAS AND BETTER UNDERSTAND STUDY THE AGE EFFECTS ON THOSE NETWORKS AS THEY CHANGE OVER TIME. THERE IS A PRESSING NEED I THINK OR WE FAILED TO LAUNCH AND CONDUCT STUDIES OF CONTINUOUS DRUG DELIVERY LOOK FOR PREVENTING DEVELOPMENT OF MOTOR COMPLICATIONS AND CHANGE HOW WE ADMINISTER DRUGS TO PARKINSON'S TODAY TO COMPLETELY PREVENT THESE PROBLEMS AND ALSO TO ONCE THEY HAVE DEVELOPED TRY AND IDENTIFY NOVEL TARGETS FOR TREATMENT AND DEVELOP NOVEL THERAPIES IN THAT ARENA AS WELCH L EVADOPA HAS THESE VEXING PROPERTIES, IT IS THE GOLD STANDARD OF SYMPTOMATIC THERAPY, THOUGH IT INDUCES PROBLEMS WE'RE TALKING ABOUT OVER TIME AND IT FAILS TO ADDRESS CERTAIN OTHER MOTOR PROBLEM OF ADVANCE PD, THAT WAS THE OTHER AREA WE DISCUSSED IN THE GROUP, LEVADOPA RESISTANT MOTOR SYMPTOMS AND OPPORTUNITIES AND CHALLENGES WE HAVE REGARDING THEIR SYMPTOMATIC TREATMENT. AND THIS IS A SLIDE REMINDING ALL OF US ABOUT THE SCOPE AND SPECTRUM OF THESE LEVADOPA RESISTANT MOTOR PROBLEMS SOMETIMES CALLED AXIAL MOTOR SIGNS AND PROBLEMS OF PARKINSON'S DISEASE, THEY INCLUDE DEFORMITIES THAT HAVE BEEN DESCRIBED AND NICELY DEPICTED IN THE OLD TEXT BOOKS OF THE 19th CENTURY ALREADY TRUNK BENCH TRUNK MORE THAN 60-DEGREES FORWARD LATERAL TRUNK FLEXION, DISTAL LIMB DEFORMITIES TERMED BY CLINICAL NEUROLOGISTS LIKE STRIATAL DEFORMITIES. RHEUMATOID DEFORMITIES AND ONE BIG PROBLEM THAT WE FACE MANY AS THE DISEASE PROGRESSES IS FREEZING OF GATING FALLING AND DISABILITY ARISING FROM THERE, FREEZING AND FALLING PATIENTS WITH ADVANCED PD IS A VERY COMMON PROBLEM WITH MORE 70% SERIES REGULAR FALLING WITH LONG STANDING PARKINSON'S DISEASE, IT IS ESTIMATED AROUND 20% PATIENTS MAY SUSTAIN FRACTURES RELATED TO FALLS. , AMONG THE COMMON REASONS FOR INSTITUTIONALIZATION OF PARKINSON'S PATIENTS AND IS CLEARLY ASSOCIATED WITH INCREASED MORTALITY. AND THERE ARE MANY UNKNOWNS ABOUT THIS PARTICULAR ARENA OF LEVADOPA RESISTANT MOTOR SYMPTOMS, FREEZING FALLING AND DEFORMITY. WE KNOW LITTLE ABOUT THE EXACT CLINICAL PATHOLOGICAL CORRELATIONS AND NEURONAL MECHANISMS THAT UNDERLIE THE DEVELOPMENT OF THESE PROBLEMS. WE DON'T KNOW WHY THERE ARE PATIENTS WHO ARE LIKELY TO DEVELOP THEM WHILE OTHER SUCCESS STUDY GO THROUGH LONG STANDING PARKINSON'S DISEASE WITHOUT SUCCESSFULLY TARGET WITH THERAPEUTIC INTERVENTIONS AND CONTROL THE MECHANISMS UNDERLYING THESE PROBLEMS. VARIETY OF RESEARCH NEEDS AND APPROACH OPPORTUNITIES WAS WORTH ADDRESSING. STUDIES IDENTIFY MARKERS RISK AND BIOMARKERS FOR THE DEVELOPMENT OF THESE PROBLEMS TO DEFINE THE NATURE OF DYSFUNCTIONAL MOTOR CONTROL THESE PATIENTS HAVE USING NOVEL COMPUTATIONAL TECHNOLOGY THAT HAS BECOME AVAILABLE. TO STUDY ASSOCIATION BETWEEN THESE LEVADOPA RESISTANT MOTOR SYMPTOMS AND NON-MOTOR PROBLEMS LIKE AUTONOMIC FAILURE AND COGNITIVE FUNCTION AND TO TRY AND IDENTIFY NOVEL TARGETS FOR BOTH PHARMACOLOGY AND DBS TYPES OF TREATMENT FOR THEM AND LASTLY BUT CERTAINLY NOT LEAST TO CONTINUE LAUNCHING TRIALS OF BEHAVIORAL AND EXERCISE-BASED TECHNIQUES TO OVERCOME AND HELP THESE NON-MOTOR LEVADOPA RESISTANT PROBLEMS. FINALLY A GROUP TO DISCUSS THE ARENA ON THE SPECTRUM OF NON-MOTOR FEATURES THAT ALSO OF COURSE IS AN IMPORTANT PART OF THE CHALLENGES OF ADVANCED PARKINSON'S DISEASE WHEN IT COMES TO SYMPTOMATIC THERAPY. MULTITUDE OF NEURONAL CELL POPULATIONS ALSO OUTSIDE THE BRAIN INCLUDING AUTONOMIC ENTERIC AND CARDIO SYMPATHETIC NERVOUS SYSTEM PRODUCING WIDE SPECTRUM NON-AUTO MANIFESTATIONS, NEUROPSYCHIATRIC AUTONOMIC SLEEP WAKE DISREGULATION. JUST NAME A FEW. WE WERE AWARE THAT NON-MOTOR SYMPTOMS OF PARKINSON'S DISEASE ARE FOR MANY PATIENTS HAVE TIDE TO CORRELATION WITH QUALITY OF LIFE AND CLASSICAL MOTOR SCALES, THEY ARE A KEY DRIVER OF DISABILITY AND COGNITIVE DYSFUNCTION AS BEING LONG IDENTIFIED A MAJOR RISK FACTOR FOR NURSING HOME PLACEMENT AND MORTALITY. AND IN CONTRAST WOULD BE ENORMOUS SIGNIFICANCE AND IMPACT MOTOR SYMPTOMS. WE HAVE FEW CLINICAL TRIALS THAT HAVE SPECIFICALLY ADDRESSED TREATMENTS, FOR THESE NON-MOTOR SYMPTOMS IN PD POPULATIONS AND WE HAVE A PAUCITY OF DATA TO GUIDE US WHEN IT COMES TO TREATMENT DECISIONS. IN TERMS OF THINGS WE NEED TO KNOW, WE HAVE LIMITED KNOWLEDGE ABOUT THE PATHOLOGICAL CORRELATIONS FOR MILLION NON-MOTOR SYMPTOMS, WE KNOW A LITTLE BIT FOR EXAMPLE ABOUT WHAT MIGHT BE RELEVANTTOR DEVELOPMENT OF ORTHO STATIC HYPERTENSION OR URINARY FAILURE IN PARKINSON'S DISEASE, BUT SITUATION IS FAR FROM CLEAR H. WE DON'T KNOW GENETIC OR OTHER RISK FACTORS FROM OTHER SPECIFIC NMS, FOR EXAMPLE, DEMENTIA, WE HAVE LIMITED KNOWLEDGE ABOUT CLUSTERING OF NMS AND HOW THAT RELATES TO PD NATURAL HISTORY AND HOW WE MIGHT USE NON-MOTOR SYMPTOM PROFILES TO SUBTYPE PARKINSON'S DISEASE. WE DON'T KNOW FACTORS THAT DRIVE PROGRESSION, AUTONOMIC FAILURE COGNITIVE DYSFUNCTION, THE TARGETS FOR DRUG TREATMENT AND PREVENTION ARE STILL ONLY PARTIALLY KNOWN AND WE NEED TO WORK ON THAT AND CERTAINLY CONTINUE LAUNCHING RANDOMIZED CONTROL CLINICAL TRIALS TO ASSESS THERAPEUTIC EFFICACY AND SAFETY. SO AGAIN, A LONG LIST OF RESEARCH APPROACHES THAT NEED TO BE TAKEN IN FUTURE PROSPECTIVE STUDIES NEEDED TO DEFINE EVOLUTION OF NON-MOTOR SYMPTOMS FROM THE VERY START OF PARKINSON'S DISEASE AND TO MAYBE SUBGROUP THE DISEASE BY NMS PROFILES. THERE ARE WAYS TO USE NEUROPHYSIOLOGY, NEUROIMAGING OTHER BIOMARKERS TO TRY AND BETTER UNDERSTAND THE NON-MOTOR SYMPTOM MECHANISMS AND RISK FACTORS AND TREATMENT TARGETS. THERE IS A NEED STILL TO USE PATIENT AND CAREGIVER INFORMATION WHEN ONE TRIES TO PRIORITIZE WHICH TYPES OF NON-MOTOR SYMPTOM CLUSTERS TO STUDY AND WE NEED TO WORK ON VALIDATION OF CONSTRUCTION AND SENSITIVE VALID INSTRUMENTS TO MEASURE NMS IN PARKINSON'S DISEASE AND THERE HAVE TO BE MORE CLINICAL TRIALS TO BOTH PHARMACOLOGY AN NON-PHARMACOLOGICAL INTERVENTIONS TO REDUCE NMS BURDEN AND PROGRESSION OF NON-MOTOR SYMPTOMS. THE DIFFERENT POSSIBLE RECOMMENDATIONS THAT CAME UP WITH SEVERAL IN THE GROUP DISCUSSION WITH THE GROUP MADE TO IT THE TOP 12 AND HERE ARE THE NUMBERS, 4, 6, 12. ARE THEY ON TARGET, TO THEY NEED TO BE MODIFIED. WE'LL LEAVE THAT SLIDE UP FOR OUR PANEL DISCUSSION. I'LL STOP HERE. THANK YOU VERY MUCH. [APPLAUSE] >> I'M GOING TO MODERATE THIS PANEL BUT P I'LL ASK FOR THE ACTIVE PARTICIPATION OF THE MEMBERS AND AS TOM MONTINE SAID, THE OTHER PANELISTS H INVITED TO COME TO MICROPHONES DURING THE DISCUSSION. DURING THE LAST FIVE MINUTES OF THE 20 MINUTE PANEL DISCUSSION, THE OTHER MEMBERS OF THE PUBLIC WHO ARE PRESENT ARE WELCOME TO COME UP TO THE MICROPHONE AND ASK QUESTIONS. AS WELL. SO WERNER, I WAS GOING TO ASK YOU THE FIRST QUESTION. THE HIGHEST RANKED RECOMMENDATION FROM YOUR WORK GROUP WAS NUMBER 4 NICHE WAIVE PERSPECTIVE STUDIES TO DEFINE NON-MOTOR SYMPTOMS. WHAT NON-MOTOR SYMPTOMS YOU HAD IN MIND AND KINDS OF APPROACHES YOU THOUGHT YOUR GROUP MIGHT TAKE TO ADDRESS THIS PROBLEM? >> FROM WHAT I UNDERSTAND IN THE PROCESS OF RANKING HIGHER UP OTHER RECOMMENDATIONS WE WERE DISCUSSING WAS AWARENESS THAT WE MAY HAVE DIFFERENT TYPES OF PARKINSON'S DISEASE BASED ON THE NON-MOTOR SYMPTOM CLUSTERS THAT ACCOMPANY THE DISEASE. WE HAVE PARKINSON'S DISEASE PATIENTS THAT MAJORITY FOR EXAMPLE SUFFER FROM COGNITIVE IMPAIRMENT AND COGNITIVE DECLINE, OTHERS DON'T. WE SEEM TO BE SEEING SOME COUPLING BETWEEN THE DEVELOPMENT OF COGNITIVE DECLINE AUTONOMIC FAILURE AND WE FELT THERE IS A NEED STILL IN PERSPECTIVE LONGITUDINAL STUDIES TO GET A BETTER HANDLE ON THE EVOLUTION OF THESE NMS CLUSTERS AND DISEASE PROGRESSES FROM EARLY ON. MOST STUDIES WE HAVE ON PATIENTS WITH ADVANCED PARKINSON'S DISEASE AND WE HAVE LITTLE IN TERM OF COHORTS STUDIED IN THAT REGARD. THAT WAS ONE PER SECTION WHY THAT IS HIGHER UP IN THE RANGING. AWARENESS OF DEFICIENCIES IN TREATMENT AND PREVENTION, WHAT ARE RISK FACTORS AND POTENTIALLY PREVENT MILESTONES TO PD EVOLUTION FOR IN PARTICULAR DEMENTIA WHICH IS A MAJOR NEED TO SOMEHOW DELAY OCCURRENCE OF COGNITIVE DECLINE DEMENTIA AND ANOTHER HIGH UP AS AN AREA OF NEED. >> THANKS. THAT'S A COMBINATION OF TREATING NON-MOTOR SYMPTOMS AND CLUSTERS OF NON-MOTOR SYMPTOMS POTENTIALLY IDENTIFY BIOLOGICALLY RELEVANT SUBTYPES. >> THAT'S A FAIR SUMMARY. >> NUMBER 6 U YOU'RE INTERESTED IN GATE AND BOUNCE PROBLEMS. TO IDENTIFY MECHANISMS FOR DEVELOPMENT OF LEVADOPA MOTOR SYMPTOMS FOR GATE AN BALANCE PROBLEMS AND DEVELOP NOVEL THERAPEUTIC APPROACHES TO THESE PROBLEMS. I WONDER IF YOU CAN TALK ABOUT WHAT YOU SEE AS BIG CHALLENGES IN GATE MAYBE MEDICINE, MAYBE NON-MEDICAL APPROACHES, TO TACKLE THE PROBLEM GOING FORWARD. >> GATE AND BALANCE REALLY ARE KEY FOR DISABILITY AND PARKINSON'S DISEASE BECAUSE YOU LOOK AT THE INSTRUMENTAL ADL, MOST OF THEM REQUIRE MOBILITY. WHEN MOBILITY STARTS TO FAIL THAT'S WHEN THERE IS A GRADUAL PROGRESSION LIKE DOMINOES, ALL SORTS OF AZLs. IS OBVIOUSLY PHARMACO THERAPIES ARE NOT AD WATT AND WE NEED NEW TOOLS. EXERCISE, PHYSICAL TRAINING, EVEN COGNITIVE TRAINING ARE INTERESTING NEW AVENUES BEGINNING TO SHOW PROMISE TO IMPROVE GATE. THERE'S ADDITIONAL WORK TO DO IN THAT AREA THAT REALLY WE NEED, FUNDING PROPERLY LOOKING TO THE HUGE RANGE OF QUESTIONS, SOME INCLUDE MANY TYPES OF PHYSICAL TRAINING LOOKED AT, MANY HAVE POSITIVE BENEFIT BUS OUR OWN WORK AT THE UNIVERSITY OF MARYLAND SHOWS THAT IT ISN'T ONE SIZE FITS ALL, THERE ARE DIFFERENCES BETWEEN THESE DIFFERENT EXERCISE REGIMENS, IN OUR CASE TREADMILL AND MUSCLE STRENGTHENINGMENT WE DID FIND THEY HAD BENEFITS BUT IN DIFFERENT WAYS. SO THERE IS A NEED TO LOOK TO UNDERSTAND WHICH PATIENTS ARE MOST LIKELY TO BENEFIT WHICH REGIMENS AND MOVE TOOLS FROM THE LAB TO THE COMMUNITY AND FIND WAYS TO ENCOURAGE PEOPLE TO THESE RECOMMENDATION MENS ON THEIR OWN AND -- REGIMENS ON THEIR OWN AND CONTINUE FORWARD. ANOTHER AREA OF INTEREST IS INTERACTION BETWEEN COGNITIVE TRAINING AND PHYSICAL TRAINING. IT IS FASCINATING THAT IN FACT COGNITIVE TRAINING HAS BEEN SHOWN TO IMPROVE MOBILITY AND PHYSICAL TRAINING, VICE VERSA, TO IMPROVE PARKINSON'S DISEASE. ONE AREA TO INTERSECT IS DUAL TASKING, VIRTUALLY EVERYTHING IS A DUAL TASK, A COGNITIVE AND MOTOR TASK SO THAT'S A TREMENDOUS NEED. LAST IS PHYSIOLOGY OF EXERCISE. IN PARKINSON'S DISEASE THAT'S FASCINATING. WHAT IS CAUSING IS REDUCTION AND GATE ECONOMY IN PARKINSON'S DISEASE? WE HAVE SHOWN AND OTHER GROUPS AS WELL, ECONOMY OF GATE IS REDUCED IN PD AND WHAT RELATIONSHIP THAT HAS TO FATIGUE IMPLY >> SO THERE'S AVENUES TO PURSUE AND RANKING. >> I'M INTERESTED THE MECHANISM WHICH PHYSICAL TRAINING AND THERAPY INTERVENTIONS WORK. THE UNDERLYING MOLECULAR OR BIOLOGICAL BASIS FOR EFFECTIVENESS OF THESE TREATMENTS. IS IT A NON-SPECIFIC EFFECT OR A SPECIFIC BRAIN CHANGE YOU CAN DETECT DURING THESE REGIMEN? CAN YOU COMMENT ON THAT? >> GREAT QUESTION. ACROSS THE WHOLE AREA OF TRAINING ASK CLINICAL TRIALS IS RELATIVELY NEW. THE AREA LOOKING AT MECHANISMS IS ALSO RELATIVELY NEW. PEOPLE ARE LOOKING AND SEARCHING FOR BETTER TOOLS IMAGING AND OTHERWISE TO BETTER UNDERSTAND THE MECHANISM CERTAINLY WHAT WE'RE SEEING IS EVIDENCE OF PLASTICITY BASED ON REPETITIVE MOVEMENT. THAT IS NOT ENTIRELY CONFIRMED YET. IN ANIMAL MODELS YES. >> ONE MORE TIME, WHAT KINDS OF STUDIES COULD YOU IMAGINE, WHAT TOOLS OR EMERGING TOOLS COULD BE USED TO ANSWER THESE QUESTIONS OR DO THEY EXIST? >> THE AREA OF FUNCTIONAL IMAGING IS PROMISING BUT PROBLEMATIC, BECAUSE IT IS EXTREMELY DIFFICULT TO IMPLEMENT MOVEMENTS OR SIMULATED MOVEMENTS LIKE EXERCISE IN ABOUT IMAGING SCANNER SO THAT IS DIFFICULT. PEOPLE ALSO USED IMAGERY TO SOME EFFECT SO THAT HAS OPPORTUNITIES AS WELL. SAME WAY THERE'S INTERESTING WORK LOOKING AT VIRTUAL STIMULATION AND EXERCISE. THERE IS A LARGE ARRAY OF OPPORTUNITIES, ANOTHER AREA WHICH WERNER MENTIONS IS THE BIOSENSORS AND THE OPPORTUNITIES TO UNDERSTAND MORE ABOUT ACTIVITY IN THE HOME. AND ANALYZE BETTER. THESE ARE ALL PROMISING AREAS. >> I WOULD LIKE TO ADD WITH RELATION TO MOVEMENT ANALYSIS WE STILL HAVE AN UNEXPLORED OPPORTUNITY TO FIND THE RIGHT WAYS OF USING COMPUTATIONAL TECHNOLOGIES TO QUEUE PATIENTS WITH FREEZING. WE HAVE ALL LAID OUR LITTLE TRIALS OF THINGS LIKE SENSORY QUEUING ACOUSTIC OR VISUAL BUT THERE'S A FUTURE FOR INNOVATIVE TECHNOLOGY THAT COULD BE USED ON A DAILY ROUTINE BASIS IN FREEZERS AND FOLDERS RELATED TO FREEZING IN RIGHT SENSE ARE U QUEUES TO OVERCOME THEIR PROBLEMS AND REDUCE MR. FALCONE: ING RATES. >> THANK YOU FOR THE DISCUSSION. KAREN, I WAS GOING TO ASK YOU TO TALK ABOUT THE PROBLEM OF COGNITIVE AND NEUROPSYCHIATRIC MOTOR FEATURES IN TERMS OF THERAPEUTICS, BIOMARKERS, MAYBE OVERLAP BETWEEN PARKINSON'S DISEASE AND LOU WII BODY DISEASE. AND YOU HAVE ABOUT A MINUTE TAKE AS LONG AS YOU LIKE. >> SOMETHING I KNOW. I THINK WHAT WE HEARD IS OBVIOUSLY COGNITIVE IMPAIRMENT IS HUGE PROBLEM, IN EARLY PD UP TO 25% MILE COGNITIVE IMPAIRMENT WHICH NEEDS TO BE VALIDATED. AS STUDIES HAVE SHOWN UP TO 80% WILL DEVELOP DEMENTIA BY 25 YEARS, SO IT'S A HUGE PROBLEM OVERLAP AS YOU HEARD WITH PSYCHIATRIC IMPAIRMENT AND OTHER IMPAIRMENTS, AXIAL IMPAIRMENT THINKING ABOUT. IN THINKING CLINICAL TRIALS, THERE'S A RECENT REVIEW THERE WERE SIX TRIALS OF COLONNEST RACE INHIBITORS IN PARKINSON'S DISEASE DEMENTIA BUT UP IN WORK IN DEMENTIA WITH LOUIS BODY SO THAT'S A MAJOR AREA OF IMPORTANCE TO ALL OF US. THE FOCUS IS PRIMARILY ON P AT LEAST IN MY OPINION ON TREATMENTS DIRECTED AT AD PATHOLOGY AND WE HAVEN'T FOCUSED AS MUCH ON PURE PD PATHOLOGY AS WE MIGHT CONSIDER. SOME OF THE GENETIC STUDIES YOU WILL HEAR LATER MAY GIVE CLUES AS TO WHAT WE SHOULD BE LOOKING AT. MUTATIONS IN GBA CLEARLY SHOWN TO BE MORE COMMON IN INDIVIDUALS WITH PARKINSON'S DISEASE DEMENTIA AND LOUIS BODY SO AN AREA CLEARLY WE NEED TO FOCUS, SORT OF THE FLIP SIDE LESS LIKELY ASSOCIATED WITH COGNITIVE IMPAIRMENT CROSS SECTIONALLY, THAT'S AN AREA TO PURSUE IN TERMS OF LONGITUDINAL STUDIES TO SEE WHAT THE PROGRESSION OF COGNITIVE IMPAIRMENT IS. BUT IT BRINGS UP THE IDEA THAT WE NEED TO PROFILE PEOPLE WITH BIOMARKERS AND THERE'S THAT INTERPLAY BETWEEN HOW WE GENERALIZE AND HOW WE BE MORE SPECIFIC BUT I THINK WE HAVE THE TOOLS AT THIS POINT IN TERMS OF CSF BIOMARKERS AN GENETIC MARKERS AND BLOOD BIOMARKERS TO BE ABLE TO ISOLATE PATIENTS WHO ARE MORE LIKELY TO HAVE AD PATHOLOGY IN SETTING OF PD AND THOSE MORE LIKELY TO HAVE THE MORE PURE FORMS OF PARKINSON'S DISEASE. ASSOCIATED WITH COGNITIVE OR PSYCHIATRIC IMPAIRMENT. AND WITH THE MULTI-CENTER STUDIES AND THE INFRASTRUCTURE CREATED THROUGH THE NINDS, THESE ARE THE DIRECTIONS WE CAN GO INTO IN TERMS OF GETTING PATIENTS, ENOUGH PATIENTS WITH THESE PROFILES TOGETHER. AND SYSTEMATICALLY USING TOOLS THE CDEs FOR EXAMPLE BILL IN THAT VEIN TO LOOK AT CLINICAL TRIALS IN THESE DISEASES. >> THE DISTINCTION AMONG THE DIFFERENT FORMS OF DEMENTIA WILL -- MAY EFFECT PEOPLE WITH PARKINSON'S DISEASE, PDD LOU WII BODY DEMENTIA AND ALZHEIMER'S DISEASE GETS TO BE CHALLENGING, EVALUATING THE PATIENT. AND IT SEEMS TO ME, CURIOUS TO KNOW WHAT YOU THINK ABOUT ADDING IN, IMAGING BIOMARKERS AN FROM THE PERSPECTIVE OF OF STUDY DESIGN TO GET A BETTER HANDLE, THE IMPORTANCE OF FOLLOWING THROUGH TO POSTMORTEM. AND HOW THAT MIGHT CONNECT. >> YOU'RE ABSOLUTELY RIGHT. I DON'T KNOW IF YOU'RE ALLOWED TO COMMENT ON THAT. THAT'S AN AREA THAT'S IMPORTANT. WE USE THE CRITERIA OUT THERE FOR DEMENTIA WITH LOUIS BODY WITH PDD BUT WE'RE LEARNING MORE AT ONLY STAGE THEY'RE SIMILAR SO IT'S VERY IMPORTANT TO CHARACTERIZE PEOPLE VERY EARLY. >> MY NAME IS RICK BURZON, SOCIAL SCIENTIST PROGRAM OFFICER NATIONAL INSTITUTE OF MINORITY HEALTH AND HEALTH DISPARITIES HERE AT THE NIH. THANK YOU VERY MUCH FOR SHARING THESE UPDATES WITH US AND BRINGING US UP TO SPEED. ON CURRENT RESEARCH AND TREATMENT. I HAD A QUESTION ABOUT PICKING UP ON QUITE A LOT OF DISCUSSION AROUND COGNITIVE IMPAIRMENT. I HAVEN'T SEEN ANY EPIDEMIOLOGY, I QUICKLY LOOK THROUGH THE PROGRAM AND I DON'T SEE ANY OF THAT. SO I WANT TO ASK YOU IF YOU CAN SHARE WITH US WHETHER OR NOT THE INCIDENCE OF PARKINSON'S DISEASE SEEMS TO BE INCREASING IN YOUNGER PATIENTS, PEOPLE, AND WHETHER OR NOT THAT IS WHAT THAT MIGHT BE ATTRIBUTED TO AND THE RISKS THAT THAT MIGHT PUT THOSE PATIENTS AT FOR SAY COGNITIVE IMPAIRMENT OR OTHER SORTS OF NON-MOTOR ISSUES WITH RESPECT TO PARKINSON'S. >> THE SHORT ANSWER TO THAT, I WOULD BE INTERESTED IN OTHER PEOPLE'S. S IS WE DON'T KNOW, BECAUSE THERE ISN'T SUFFICIENT PERSPECTIVE ASSESSMENT OF DISEASE INCIDENCE TO BE ABLE TO MAKE A VALID COMMENT ABOUT THAT. PARKINSON'S DISEASE ISN'T REPORTED. EVEN LOOKING AT MEDICARE, YOU'RE NOT TRACKING THE UNDERAGE AT ONSET SO IT'S DIFFICULT TO COMMENT ON THAT. I THINK YOU CAN HYPOTHESIZE LOOKING AT ONE SINGLE ENVIRONMENTAL RISK FACTOR TRAUMATIC BRAIN INJURY, THERE IS A GOOD CHANCE THERE IS INCREASE AT YOUNGER AGE ONSET AND PEOPLE WITH COGNITIVE IMPAIRMENT AND PARKINSON'SISM MILITARY POP LATION BUT WE DON'T KNOW, THAT'S AN IMPORTANT AREA TO STUDY. >> THAT'S A NUMBER OF PEOPLE WITH A NUMBER OF QUESTIONS. I WOULD LIKE TO TOUCH ON RECOMMENDATION NUMBER 12 BEFORE WE DO THAT. DON'T SIT DOWN, IT WON'T TAKE LONG. PHIL STARR, ARE YOU ON THE PHONE? FROM I AM. >> I WANT TO ASK YOU A QUESTION ABOUT WHAT IS GOING ON WITH SURGICAL THERAPIES AND MOLECULAR BASED IMPLANTED THERAPIES IN GENERAL REGARDING RECOMMENDATION NUMBER 12, IDENTIFY RISK FACTORS AND PATHOGENIC MECHANISMS FROM MOTOR FLUCTUATIONS AND DYSKINESIAS AND NOVEL TARGETS FOR SYMPTOMATIC THERAPY FOR THESE PROBLEMS. I WONDER IF YOU CAN TALK ABOUT SURGICAL TREATMENTS FOR PARKINSON'S DISEASE IN THE PAST AND GOING FORWARD IN THE CONTEXT OF MOTOR COMPLICATIONS INCLUDING DYSKINESIAS AND FLUCTUATIONS. >> I THINK SURGERY IS A HUGE ADVANCE TREATING THE MOTOR FLUCTUATION PROBLEM THAT WAS GONE OVER IN TERMS OF LEVADOPA INDUCED COMPLICATIONS SO WE HAVE GOOD SURGICAL THERAPIES WITH BASAL GANGLIA STIMULATION FOR MOTOR FLUCTUATION AND DYSKINESIA PROBLEM. THEY'RE NOT PERFECT BUT THEY'RE GOOD IN THE STUDIES THAT WERE ALREADY OUTLINED. SO WHERE WE NEED TO GO WITH SURGICAL THERAPY IS WHAT WAS OUTLINED WITH MEDICAL THERAPY STARTING TO I DRESS PROBLEMS OF -- ADDRESS PROBLEMS OF PROGRESSION AN NON-P MOTOR SYMPTOMS AND MOTOR SYMPTOMS THAT ARE RESISTANT TO CURRENT THERAPY SO THERE'S GATE DISORDERS AND WORK WITH ALTERNATIVE DEEP BRAIN STIMULATION TO TRY FREEZING OF GATE OR POSTURAL INSTABILITY SUCH AS THE STRUCTURAL NUCLEUS. THAT'S NOT A HOME RUN, SOME INTERESTING RESULTS BUT MORE WORK NEEDS TO BE DONE. THEN WITH THE SURGICAL EMPERIMENTAL SURGICAL THERAPIES FOR GROWTH FACTOR, INFUSION, THAT IS THOSE STUDIES PROCEEDING, THOSE ARE DESIGNED TO ADDRESS CLASSIC MOTOR SYMPTOMS OF PARKINSON'S. >> THANKS. SO JOHN YOU WERE NEXT. >> JOHN (INDISCERNIBLE) FROM UNIVERSITY OF PENNSYLVANIA UDOLF CENTER. I WOULD LIKE TO OFFER MY PERSONAL THANKS TO STORY AND EVERYONE AT NINDS PUTTING THE MEETING TOGETHER TOM MONTINE FOR HIS LEADERSHIP. THIS IS REALLY IMPORTANT STUFF WE'RE TALKING ABOUT. I HAD A QUESTION ABOUT WHETHER Y'ALL HAVE DONE QUERIES WITH PARKINSON'S PATIENTS THAT I GUESS YOU HAVE TO DO DIFFERENT STAGES OF THE DISEASE TO SEE HOW THEY RANK ORDER THE VARIOUS MOTOR AND NON-MOTOR ISSUES THAT COME UP DURING PARKINSON'S DISEASE. I'M NOT AWARE, MAYBE THERE IS A LITERATURE, WHAT CAREGIVERS VERSUS THE PATIENTS THEMSELVES CONSIDER THE MOST PRESSING URGENT PROBLEMS OF THE DAY. THAT WILL PROBABLY BE VERY DIFFERENT THAN FIRST FIVE YEARS OF PARKINSON'S DISEASE VERSUS THE 20 OR 15 YEARS OUT BUT CURIOUS IF THERE ARE DATA ABOUT PATIENT PERCEPTIONS OF WHAT MOST URGENT IN THEIR EYES TO ADDRESS. >> WE'LL HAVE A BROAD DISCUSSION. >> SO THAT IS A TIMELY QUESTION. Z MOST OF US KNOW THE CONCEPT OF PATIENT CENTERED MEDICINE AND PATIENT REPORTED OUTCOMES IS HAVING ITS DAY. I THINK IN OUR PROCESS THUS FAR, WE HAVE NOT HAD ADEQUATELY PATIENT VOICE. MY UNDERSTANDING IS THAT'S PART OF WHAT WE'RE DOING NOW WITH OPENING UP TO OTHERS HERE WHO PERHAPS ARE PATIENTS OR CAREGIVERS WHO RENT PATIENTS AND CAREGIVERS. IT'S VERY IMPORTANT. THERE IS DATA THAT'S LOOKED AT BUT NOT A LOT. MICHAEL LOGAN HAS A PAPER ON THAT, BUT I DON'T REMEMBER WHAT WERE RANKED THE TOP. BUT YOU ARE RIGHT SAYING THIS NEVADA TABLY TURNS UP SURPRISES NOT FROM A CLINICIAN OR SCIENTIST POINT OF VIEW IS THE MAIN PROBLEM. >> IN THE INTEREST OF TIME WE SHOULD HOLD THIS TOPIC, I THINK IT'S -- WE HAVE A -- THE WHOLE SESSIONING THE WHOLE PANEL TO TALK ABOUT IS INTERESTING. WE HAVE TIME FOR ONE MORE QUESTION THEN WE SHOULD WRAP UP. GO AHEAD. >> >> BILL DOWER, UNIVERSITY OF MICHIGAN. FIRST I WOULD LIKE TO THANK THE PANEL FOR BRINGING UP IN PARTICULAR DEMENTIA BECAUSE EVEN AMONG FELLOW NEUROLOGISTS I'M SURPRISED HOW FEW PEOPLE APPRECIATE HOW COMMON DISMAN IS IN PARKINSON'S SO VERY MUCH SUPPORT THE HIGH RATING THERE. I WONDER WHETHER YOU MIGHT CONSIDER THOUGH COMBINING NUMBERS FOUR AND SIX IN SOME WAY BECAUSE MY VIEW THE MAJOR AXIS IS LEVADOPA RESPONSE NON-MOTOR, AND THOSE ARE THINGS THAT DON'T GET HELP HELP BY THE SURGICAL THERAPIES THEY HAVE, AND IT MIGHT ALSO HELP EMPHASIZE THE FACT EMPHASIZE THE FACT THAT THESE COGNITIVE THINGS DON'T RESPOND TO ANY THERAPIES THAT WE HAVE. I ALSO THINK THIS BRINGS UP A POINT NOT TO SAY DOPAMINE ISN'T INVOLVED BECAUSE IT MAYBE INVOLVED IN A MULTI-SYSTEM WAY WITH OTHER SYMPTOMS BUT ALSO BRINGS UP SOMETHING HIGHLIGHTED BETTER. THE NEED OF PATIENTS OVER LONGITUDINAL AS SUGGESTED BEFORE ON MULTIPLE THINGS WHETHER BETA AMYLOID, DOE PA IMAGING COLINERGIC, MANY THINGS IN THE SAME COHORT OF PATIENTS. ONE THEME I DON'T SEE THAT IS VERY IMPORTANT THOUGH THERE'S TALK AMONG US IN THE IMMUNITY, THE QUOTE UNQUOTE MULTI-SYSTEM NATURE OF ILLNESS, I DON'T THINK THERE'S ENOUGH SPECIFIC RESEARCH ON LOOKING AT HOW THESE DIFFERENT SYSTEMS INTERACT SO YOU CAN'T JUST ADD THEM IN A PREDICTABLE WAY, UNDERSTANDING FROM THE ACTUAL PATIENTS WHAT THE BALANCE OF DIFFERENT LESIONS ARE AND HOW THEY LEAD TO PHENOTYPES IS IMPORTANT TO UNDERSTANDING HOW THESE INTERACT. THAT KIND OF CLINICAL DATA IS CRITICAL FOR PEOPLE AT MORE BASIC LEVEL TRYING TO UNDERSTAND THAT. ANY COMMENTS SO FORTH ARE APPRECIATED. >> I THINK YOU'RE RIGHT. COMBINING 4 AND 6 IS A REASONABLE THING TO DO. >> DURING THE NEXT PANEL TALKING CLINICAL TRIAL METHODS, THIS PATIENT SELECTION ISSUE BASED ON FEATURES IS VERY IMPORTANT. ONE LAST POINT THINKING DESIGN OF STUDIES ADDRESSING THESE NON-MOTOR SYMPTOMS. MANY ARE SOMETIMES MANIFEST AFTER THE DIAGNOSIS OF MOTOR PARKINSON'SISM BUT MAY PROCEED DIAGNOSIS OF PARKINSONISM BY MANY YEARS OR DECADES. AUTONOMIC FEATURES DEPRESSION ANXIETY. THAT'S ANOTHER IMPORTANT TO KEEP IN MIND. THE NEXT PRESENTATION IS GIVEN BY CHRIS COFFEE IN IOWA. SO IT WILL BE A SLIDE AND CHRIS'S VOICE YOU'LL HEAR OVER THE LOUD SPEAKER. CHRIS AS YOU MAY KNOW IS A STATISTICIAN WHO HAS BEEN THE LEAD STATISTICIAN ON A NUMBER OF NINDS SPONSORED STUDIES. >> THANKS. I'M HERE. CAN EVERYONE HEAR ME? HELLO? >> CAN EVERYONE HEAR ME? >> YES. >> GREAT. YOU GOT THE STATISTICIAN WHO IS NOT THERE, THAT'S A BLESSING. SO I'M GOING TO TALK ABOUT THE SUMMARIES FROM THE TRIAL DESIGN P SUBGROUP NEXT SLIDE. SO WHAT I WANT TO DO FIRST IN CONTEXT IS REVIEW FOR MANY IN ATTENDANCE BUT MAYBE HELPFUL FOR SOME IS TO GIVE A VERY BRIEF SUMMARY OF THE DRUG DEVELOPMENT PROCESS, SO WE THINK OF IT ALTHOUGH DEVIATES SOME TRADITIONALLY IN PHASES, THE WORD PHASE 1 IS FOCUSING MORE ON THIS SAFETY TOXICITY PROFILE OF NEW INVESTIGATIONAL AGENTS, THE FIRST IN HUMAN STUDIES FOR MAXIMUM TOLERATED DOSE. OTHER TARGETS TO DETERMINE WHETHER IT'S SAFE TO GIVE AN INTERVENTION. NEXT SLIDE, PLEASE. I THINK TOO REALLY IMPORTANT IN DEVELOPMENT OF PARKINSON'S DISEASE AT THE MOMENT WHICH IS THE PROOF OF CONCEPT STAGE WHERE YOU'RE CONTINUING TO LOOK AT SAFETY, BUT ALSO STARTING TO LOOK AT WHETHER THERE IS SUFFICIENT EVIDENCE OF A BIOLOGIC ACTIVITY OR EFFECT IN ORDER TO JUSTIFY PROCEEDING TO THE LARGER MORE EXPENSIVE PHASE 3 STUDIES. NEXT SLIDE. THEN THE PHASE 3 STUDIES ARE THE BIG CONFIRMATORY TRIALS WE TEND TO THINK OF FOR INSTANCE APPLICATIONS FOR FDA LICENSESURE TO LOOK AT OVERALL BENEFIT TO RISK ASSESSMENT, LARGE MULTI-SITE STUDIES WITH SAMPLE SIZE TRYING TO DETERMINE WHETHER THERE'S SUFFICIENT EVIDENCE OF EFFICACY TO SUPPORT APPROVAL OF NEW DRUG APPLICATION. NEXT SLIDE. ALSO PHASE 4, LESS RELEVANT, LONG TERM SURVEILLANCE STUDIES POST MARKETING STUDIES, FOR BASICALLY WHETHER THERE'S ADDITIONAL DRUG CONCERNS ONCE THE DRUG IS APPROVED BECAUSE YOU CAN NEVER TRULY SHOW SAFETY IN A CLINICAL TRIAL. THAT'S THE CLINICAL TRIALS 101, JUST LAY THE STAGE. NEXT SLIDE WHAT I PUT ON THE SLIDE I WON'T SPEND TIME TALKING ABOUT MANY OF THESE, MANY EXAMPLES OF THE TYPE OF TRIAL DESIGNS USED VARIOUS PD STUDIES. EARLY SELECTION DESIGN USING THOSE TO SELECT TREATMENTS THAT HAVE A BEST RESPONSE. THESE ARE USED TO ADDRESS THE PIPELINE PROBLEMS OF MULTIPLE TREATMENTS THAT WE COULD CONSIDER PROMISING FUTURE RESOURCES ON. THERE'S MULTI-DOSE PAIR HELL ARM STUDY LOOKING AT MULTIPLE DOSES. AT A SINGLE TIME. THERE'S FUTILITY AND NON-SUPERIORITY DESIGNS YOU'LL TALK MORE ABOUT IN JUST A MINUTE. NEXT SLIDE, PLEASE. FOR CONFIRMATORY DESIGNS A LOT OF THESE OTHER DISEASE AREAS SUCH AS TWO BY TWO FACTORIAL DESIGN OR RANDOMIZED PLACEBO DESIGN, OTHERS NUANCES TREATING PD SUBJECTS DELAYED START DESIGN CENTRAL THEME THAT COMES UP IN THE CLINICAL TRIAL METHODS SITUATION WHICH IS STANDARD DESIGN MAY NOT BE OPTIMAL FOR SPECIFIC DISEASESES AS IMPORTANT TO THE SPECIFIC OF THE DISORDERRER YOU'RE LOOKING AT TO LOOK AT THE MOST EFFICIENT DESIGNS. NEXT SLIDE. TO GIVE AN EXAMPLE TO EXPAND A BIT ON THESE FOR FUTILITY DESIGN, IT FLIPS WHAT WE TYPICALLY THINK OF ONE OF THESE PROOF OF CONCEPT STUDIES ARE APPROACHED WE THINK EVERYONE IS CONVINCED THE NEW TREATMENT WORKS THE INVESTIGATOR LEADING THE STUDY AND WE TEND TO LOOK AT THESE AS WE'RE LOOKING FOR A JUSTIFICATION TO GO FORWARD TO PHASE 3. AND UNLESS THERE'S CLEAR EVIDENCE THAT NOTHING IS PRESENT IT WOULD GO FORWARD. THE OPPOSITE APPROACH IS ONE THAT MIGHT -- SOME WOULD ARGUE WE NEED TO CONSIDER MORE UNLESS THERE'S CONVINCING EVIDENCE THAT IT SHOULD GO FORWARD IT SHOULDN'T GO FORWARD. THERE'S TRADE OFFS BETWEEN TYPE 1 ERRORS TYPE 2 AND SO FORTH BUT FUTILITY DESIGN TRIES TO ADDRESS THAT IN SOME WAY YOU SET UP AND SAY CAN I SHOW THAT IN A SMALLER STUDY THAT CLEARLY THE SIZE OF EFFECT I NEED TO HAVE IN ORDER TO JUSTIFY LICENSURE OF A DRUG IS NOT PRESENT. SO IF YOU REJECT FOR FUTILITY, THAT WOULD SAY THAT IT'S NOT LIKELY TO SHOW EFFICACY YOU WOULD NOT GO FORWARD WITH A PHASE 3 STUDY. IF YOU DON'T SHOW FUTILITY IT DOESN'T SHOW THE TREATMENT IS EFFECTIVE. IT SHOWS ENOUGH EVIDENCE TO MOVE FORWARD SO IT'S A NICE GATEKEEPER DESIGN WHICH GIVES YOU A GOOD GO, NO GO DECISION TO JUSTIFY EXPENSE TO MOVE TOWARD PHASE 3 DESIGN. OTHER TYPES OF DESIGN BUT IN PARTICULAR A LOT OF TAKES PLACE WITH MORE EFFICIENT PHASE 2 DESIGN THESE PROOF OF CONCEPT IS REALLY IMPORTANT BECAUSE EVERYONE PROCEEDS THROUGH TO PHASE 3, BOTH THE COMPANY, INVESTORS WHO PUT RESOURCES IN THAT AND THE PATIENTS AND ADVOCACY GROUPS WHO ARE DISAPPOINTED BY TRIAL RESULTS. NEXT SLIDE PLEASE. MOVING THE TYPES OF INFORMATION, NEXT SLIDE, THAT WE DON'T FOR BIOMARKERS IS AN IMPORTANT AREA ALLUDED TO IN IN THE PREVIOUS DISCUSSION. BIOMARKERS TO DETERMINE WHETHER EXPERIMENTAL AGENT ENGAGING BIOLOGICAL TARGET, SO THIS IS A WAY TO LOOK FOR THE EFFECT OF P AN INTERVENTIONAL AGENT AND ALSO BIOMARKERS USED TO SCREEN POTENTIAL AGENTS FOR PD. SO IN PARTICULAR WHAT WOULD BE NICE FROM A TRIAL DESIGN AND FROM A TRIAL CONDUCT STANDPOINT IN THE DRUG DEVELOPMENT REALM IS TO HAVE BETTER BIOMARKERS WHERE SHORT TERM CHANGES AND BIOMARKER MAY CORRELATE LONG TERM CHANGES WITH MEASUREMENT LIKE THE MDS UPRS WHICH CASE STUDIES USE THE BIOMARKER AS THE END POINT WHICH IS CONDUCTED IN A SHORTER TIME FRAME AND GET THE INFORMATION WHICH IS MUCH MORE EFFICIENT. NEXT SLIDE. THE NEXT SET OF INFORMATION IS THE ASSESSMENT OF STUDY DESIGN SO IT'S ONE TO COME UP WITH A TRIAL DESIGN IN A TREATMENT STUDY BUT IF IT FAILS IT'S NOT CLEAR WHETHER IT WAS THE TREATMENT OR DESIGN THAT IS FAILING. IF THE TREATMENT ITSELF IS FAILING, DOESN'T WORK, ALTHOUGH DISAPPOINTING TO FIELD, IT IS SOMETHING EVERYONE CAN LIVE WITH. WHAT WE WOULD LIKE TO AVOID IS IF A TREATMENT WORK BUS THE TRIAL IS NEGATIVE BECAUSE THE DESIGN WAS NOT APPROPRIATE OR HAD FLAWS TO AVOID FINDING THE TREATMENT WORKS IS THE WORST CASE SITUATION SO ASSESSMENT DESIGN ONE THING THAT IS DONE SOMEWHAT BUT NOT TO LEVEL HELPFUL, PARTICULARLY WITH THESE NUANCE DESIGNS IS AS NEW DESIGNS ARE PROPOSED, HAVING MORE RIGID EVALUATION OF DESIGNS THROUGH SIMULATION STUDIES BASED ON ASSUMPTIONS AN EXPECTATIONS BASED ON PROGRESSION OF THE DISEASE WHICH TIES IN TO SOME OF THE OTHER INFORMATION NEEDED TO BETTER UNDERSTAND PROGRESSION, AS WELL AS THE MECHANISM BY WHICH AN INTERVENTION MAYBE EXPECTED TO WORK. IF YOU CAN SHOW IF THE WAY WE EXPECT A TREATMENT TO WORK ACTUALLY HAPPENS THAT THE DESIGN WOULD BE APPROPRIATE IN ORDER TO SHOW THAT. THAT WOULD GIVE US A BETTER SENSE THAT THEN NEGATIVE IN THAT IT DOESN'T GIVE YOU STATISTICALLY SIGNIFICANT RESULTS AT THE END OF THE STUDY WE CONCLUDE THE TREATMENT ITSELF DOES NOT WORK, IS NOT A FALLACY OF THE DESIGN. NEXT SLIDE, PLEASE. THE LAST IS KIND OF ACCESS TO EXISTING PD DATA. THIS IS TAKING UNTO ACCOUNT SYNERGY OF THE EFFORTS. HAVING ACCESS ON THE HISTORY OF PD BEFORE AN AFTER DIAGNOSIS, SOME BEING ADDRESSED CURRENTLY AS PART OF THE PPMI PROJECT THROUGH THE MICHAEL J. FOX FOUNDATION WHICH HELPS FOR WHEN DESIGNING TRIALS HAVING ACCESS TO INFORMATION BOSS NATURAL HISTORY OR THROUGH OTHER TRIALS THAT CAN BE USED TO ASSESS THE ASSUMPTIONS, DESIGN ACE LEWDED TO A MINUTE AGO AS WELL AS HAVING INFORMATION ACROSS MULTIPLE TRIALS THAT COULD BE PULLED TOGETHER TO ADDRESS QUESTIONS OF INTEREST OR HELP WITH PLANNING OF OTHER STUDIES. THIS IS TO THE COMMON DATA ELEMENTS INITIATIVE THAT DR. LANDIS MENTIONED WHICH GIVE A SENSE OF DIFFERENT GROUPS ON DIFFERENT STUDIES WOULD HAVE COMMON STRUCTURE SO IT WOULD BE EASIER TO COMBINE THOSE DATA SETS IN THE FUTURE WHEN LOOKING AT VARIOUS QUESTIONS. ADMINISTRATIVE SOURCES, THIS IS NOT SOMETHING BEING ADDRESSED IN THE PD SETTING BUT ALSO IN OTHER SETTINGS HOW TO USE ELECTRONIC MEDICAL RECORDS, OTHER TYPES OF INFORMATION TO ADD TO THE RICHNESS OF THESE DATA SETS. IN TERMS HOW WE DEVELOP BIOMARKERS WE NEED FOCUSED EFFORTS TO DEVELOP IMAGING OTHER ASSAYS FOR A LIMITED SET OF DEFINED TARGETS THAT MIGHT BE -- THAT MIGHT HAVE A ROLE IN DISEASE MODIFICATION. AS WELL AS FOCUS EFFORTS OF EVOLVING BIOMARKERS FROM AD AND NEURODEGENERATIVE DISORDERS. A LOT AS ALLUDED TO, A LOT OF INITIATIVES UNDERWAY TO ADDRESS THAT, RECEIVING SOME ATTENTION. NEXT SLIDE. DEVELOPING DESIGN METHODOLOGIES SO THIS GETS TO TWO LEVELS. ONE I ALLUDED TO BEFORE, ASSESS MENT OF DESIGN THROUGH SIMULATION STUDY BUS DEVELOPMENT OF DESIGNS COMING UP WITH IMPROVED DESIGNS. IT'S IMPORTANT TO HAVE SYNERGY BOTH CLINICAL EXPERTS, THE STATISTICIANS AS WELL AS PER SPECK ADVOCACY GROUPS, PD OTHER SETTINGS, ARE DONE INDEPENDENTLY. STATISTICIAN WORK ON DESIGN, THEN PLUGGED INTO THE STUDY BUT THERE'S NOT A LOT OF DISCUSSION TO MAKE SURE DESIGNS ARE OPTIMIZED FOR THE PARTICULAR DISEASE AREA. SO NICE TO HAVE MORE SYNERGISTIC INTERACTION BETWEEN CLINICIAN, STATISTICIAN, ADVOCACY GROUP SO FORTH TO MAKE SURE VARIOUS INFORMATION, VARIOUS ISSUES THINGS THAT NEED TO BE ADDRESSED ARE ALL ACCOUNTED FOR. SO NOT JUST MATHEMATICAL EXERCISE. NEXT SLIDE. THE OTHER WHICH IS CRITICAL, ACROSS DIFFERENT DISEASE AREAS IS IMPROVED INFORMATICS CAPABILITY SO THIS GETS TO THE CENTRAL REPOSITORY. STANDARDIZED ARCHIVED EXISTING FEATURE TRIAL DATA, HAVING CENTRAL BODY THE MANAGE STANDARDIZING OF DATA SETS, SO ONE OF THE THINGS THAT WE HAVE ENCOUNTEREDDED IN OUR LIMITED EXPERIENCE WITH THE COMMON DATA ELEMENTS IS THEY COME IN MUCH EASIER SITUATION TO COMBINE DATA SETS FROM DIFFERENT STUDIES BUT STILL NOT AS SIMPLE AS YOU JUST TAKE THE DATA SETS AND COMBINE THEM TOGETHER. IT TAKE AS LITTLE BIT OF DATA MANAGEMENT EXPERTISE, PROGRAMMING EXPERTISE TO DO THAT, TO BE HELPFUL IF THERE WAS SOMEONE CENTRALIZED TO HELP TO DO THAT. SUPPORTING DEVELOPMENT OF INFORMATICS ARCHIVE OF DATA SOURCES, ETHICAL CHALLENGE, DEIDENTIFICATION OF DATA, SOME OF THIS HAS COME UP IN PAST DISCUSSIONS IN PROJECTS WHEN YOU GET TO PARTICULARLY LOOKING AT GENETIC COHORTS, ADDITIONAL ISSUES COME UP WITH RESPECT TO THAT. NEXT SLIDE. SO BASED ON THIS, THE ROLE BECAME FROM THE RECOMMENDATIONS THROUGH THE TRIAL METHOD SUBGROUP OR THESE THREE, THESE WERE RANKED 5, 7, 10 IN THE FINAL RANKING, NUMBER 5 WHICH WAS DEVELOP BIOMARKERS OFFER TARGETED ENGAGEMENT AND PHARMACODYNAMIC EFFECTS FOR EARLY STAGE CLINICAL TRIALS. RECOMMENDATION 7 HAD TO DO WITH DEVELOPING IMPROVED METHOD WHICH INCLUDE MORE EFFICIENT STRATEGIES STORE SCREENING POTENTIAL AGENTS AND GIVEN THE ABILITY TO CONDUCT THE TYPES OF TRIAL DESIGN STIMULATIONS THAT I ALLUDED TO BEFORE TO MAKE SURE TRIAL DESIGNS ARE APPROPRIATE FOR LOOKING AT THE LONG TERM BENEFIT. THEN NUMBER 10 IS A BROAD RECOMMENDATION THAT COVERS DIFFERENT IDEAS TO DEVELOP IMPROVED INFORMATICS CAPABILITIES WHICH INCLUDE EXPLORE AGOS TYING IN WITH THE BIG DATA INITIATIVES TO MINE A LOT OF POTENTIAL DATA SETS AND PD LOOKING AT WAYS TO TEASE OUT QUESTIONS FROM LARGE DATA THAT MIGHT BE AVAILABLE. LOOKING HOW TO FURTHER DEVELOP AND PROMOTE ACCESS TO CENTRAL DATA REPOSITORY MENTIONED BEFORE. WHICH WOULD ALSO THEN PROVIDE A RESOURCE FOR THE TRIAL DESIGN SIMULATION. SO A LOT OF THESE RECOMMENDATIONS THOUGH SEPARATE THERE IS OVERLAP BETWEEN THESE AND WITH RECOMMENDATIONS FROM THE OTHER GROUPS. SO I WILL PAUSE AND WE CAN DISCUSS MORE IN THE PANEL. >> THANK YOU, CHRIS, TERRIFIC. EASY TO HEAR YOU IN THE ROOM AS IF YOU WERE HERE. BEFORE WE START THE PANEL I HAVE A HOUSEKEEPING NOTE WHICH IS FOR PEOPLE LISTENING BIVIA THE INTERNET AND YOU WANT TO ASK A QUESTION, THERE IS A EMAIL PD 2014@MAIL.NIH.GOV. EMAIL YOUR QUESTIONS TO THIS WEBSITE, WE WILL BE ABLE TO ADDRESS THE QUESTIONS DURING THE END OF THE QUESTION-AND-ANSWER SESSION OF THIS PANEL. SO FEEL FREE TO DO THAT. THE OTHER THING TO MENTION IS CHRIS COFFEY ON THE PHONE CAN ONLY HEAR IF WE USE THE MICROPHONE SO PLEASE BE USE TO USE THE MICS WHEN SPEAKING. GOOD PRACTICE ANYWAY. SO LET'S KICK OFF, WE HAVE THREE RECOMMENDATIONS RELATED TO THIS SESSION. 5, 7, AND 10. ESPECIALLY NUMBER 5 WAS GREAT INTEREST TO US AND ALSO BASIC AND TRANSLATIONAL WORKING GROUPS THAT REPRESENTS A POINT OF OVERLAP ACROSS ALL THREE GROUPS TO DEVELOP BIOMARKERS OF TARGET ENGAGEMENT AND PROXIMAL PHARMACODYNAMIC EFFECTS FOR USE IN EARLY STAGE CLINICAL TRIALS RANDY BATEMAN MY CO-CHAIR WHO I'M SORRY IS NOT HERE TOGETHER WHO IS A GREAT PARTNER TO WORK WITH, BEFORE HE WAS DOMINANTLY INHERITED ALWAYS L HAMMERER'S GROUP WAS ALSO A PHARMACO -- PHARMACOLOGIST. I WANT TO KNOW IF RANDY WOULD COMMENT ON THIS ISSUE ABOUT THE NEED FOR BIOMARKERS FOR BOTH EARLY AND LATE-STAGE DISEASE AND MAYBE DRAW PARALLELS BETWEEN THE SITUATION PARKINSON'S AND ALSO ALZHEIMER'S AND HOW IT IS IMPORTANT FOR DRUG DEVELOPMENT. RANDY, ARE YOU THERE? >> YES. >> DO YOU THINK YOU CAN ADDRESS THIS? IT'S A BIG TOPIC. BIOMARKERS OR EARLY STAGE TRIALS. >> IT IS A BIG TOPIC BUT IT IS OF IMPORTANCE BECAUSE THE ABILITY TO KNOW WHETHER A DRUG -- >> RANDY, A LITTLE LOUDER, PLEASE. THANKS. >> CAN YOU HEAR ME BETTER NOW? >> GREAT. YES. SO THE ABILITY TO TEST WHETHER A DRUG REACHES ITS TARGET WHAT IT'S TRYING TO DO IN THE BRAIN AND GETTING TYPE THE BRAIN IS OUT MOST IMPORTANCE. IF DRUG CAN'T REACH THE BRAIN AND AFFECT THE TARGET IT WAS DESIGNED TO DO THERE'S LITTLE CHANCE THAT DRUG WOULD HAVE THE DESIRED CLINICAL BENEFIT. SO THE RECOMMENDATION FOR MEASURING THE PHARMACODYNAMIC ACTION OF THE DRUG IS REALLY ONE OF THE KEY STEPS THAT I BELIEVE IN DRUG DEVELOPMENT FOR A DISEASE. THIS IS TRUE IN ALZHEIMER'S DISEASE AS IT IS TRUE IN PARKINSON DISEASE AND OTHER AREAS. THE CHALLENGE THAT WE HAVE IS THAT PARKINSON'S DISEASE IS A DISEASE OF THE BRAIN WHICH IS DIFFICULT TO GET DIRECT ACCESS TO IN CLINICAL STUDIES. SO TO DEVELOP THE ABILITY TO MEASURE THE EFFECT OF THE DRUG OF THE BRAIN ARE KEY IN DEVELOPMENT PROCESS. ALZHEIMER'S DISEASE VARYING IMAGING AGENTS AS WELL AS SPINAL FLUID MARKERS ABOUT OTHER MODALITIES HAVE BEEN DEVELOPED TO TRACK ABILITY OF DRUGS TO HAVE THEIR AFFECTS AND THIS HAS BEEN DONE IN PARKINSON'S DISEASE TO A CERTAIN EXTENT BUT I BELIEVE THIS RECOMMENDATION IS REALLY TO TRY TO BOLSTER THE ABILITY TO TRACK IN A QUANTITATIVE WAY HOW DRUGS AFFECT THE TARGET IN THE BRAIN AND TO DETERMINE AT EARLY STAGE HOW LIKELY THEY ARE TO HAVE A CHANCE BEING CLINICALLY BENEFIT OFFICIAL FOR PATIENTS IN LARGER AN LONGER LATER STAGE CLINICAL TRIALS. >> RANDY, IN MY WORK NOW WE SPEND TIME ON BIOMARKERS AND A LOT OF TIMES LOOKING AT BIOMARKERS WHICH MEASURE THE STATE OF A CERTAIN PATIENT AMYLOID PRESENT, AMYLOID ABSENT YOU CAN SEE HOW MUCH AMYLOID IS PRESENT. SAME WITH TAU IMAGING. THIS BIOMARKER WHERE YOU SEE THE STATE OF THE PATHOLOGY IS USEFUL FOR EARLY STAGE DEVELOPMENT OR DO YOU THINK BIOMARKERS THAT MEASURE TARGET ENGAGEMENT OR RATE OF METABOLIC PROCESS LIKE DEPOSITION OF TAU AND SYNUCLEIN AND PARKINSON'S DISEASE DISEASE ARE MORE RELEVANT. HOW WOULD YOU THINK THE STATE BIOMARKERS ARE USEFUL FOR DRUG DEVELOPMENT VERSUS MORE MECHANISTIC BIOMARKERS? >> I BELIEVE THAT BOSS STAGE AS WELL AS WHETHER WE CALL THEM PROGRESSION OR MECHANISTIC BIOMARKERS IS A MAÖTER OF UTILITY, THEY ARE ALL USEFUL AND DEPENDS HOW THEY'RE USED. SO FOR EXAMPLE, RECENT ALZHEIMER'S DISEASE TRIALS, IT'S DOCUMENTED THAT 30% OF THE PATIENTS ENROLLED IN DISEASE MODIFYING TRIALS DON'T HAVE ALZHEIMER'S DISEASE. THIS IS A MAJOR CONCERN OBVIOUSLY BECAUSE THOSE INDIVIDUALS HAVE A VERY LOW LIKELIHOOD OF RESPONDING TO THE THERAPEUTICS SO A STATE BIOMARKER ONE DEFINE AMYLOID OR ALPHA SYNUCLEIN IMAGING IS HELPFUL IN SCREENING PARTICIPANTS AND INDIVIDUALS WHO WOULD BE APPROPRIATE FOR DISEASE MODIFYING TRIALS. SO IN A PHASE 3 TRIAL STATE BIOMARKER COULD BE VERY HELPFUL FOR INCLUSION OF PATIENTS WHILE IN EARLY STAGES OF DEVELOPMENT, IN PHASE 2 STUDY WHERE IS THE GOAL IS TO DETERMINE WHETHER THE DRUG IS ENGAGING WITH ITS TARGET AND DECK EARLY CHANGES WE MAY NEED MORE PROGRESSION OR MECHANISTIC BIOMARKER TO TRACK THE DISEASE AND CHANGES IN TIME TO DETERMINE THE DRUG EFFECT. IN SOME CASES THE STATE AND MECHANISTIC BUOY MARKERS MAYBE THE SAME. IT MAYBE THAT STATE BIOMARKER THAT TELLS YOU WHETHER SOMEONE HAS THE DISEASE OR NOT IS USEFUL AS PROTRACTING THAT -- FOR TRACKING THAT DISEASE PROGRESS IN TERMS OF DRUG INTERVENTION. WE ALSO SOMETIMES TURN BIOMARKERS AT PRIMARY BIOMARKERS OR BIOMARKERS THAT TARGET ENGAGEMENT VERSUS DOWNSTREAM OR SECONDARY BIOMARKERS. SO WHAT'S NEEDED IN THESE TRIALS IS THE ABILITY TO TRACK DISEASE PROCESS AS IT GOES FORWARD IN A QUANTITATIVE FASHION TO INFORM US ABOUT HOW THE DRUG IS WORKING AND QUANTITATIVELY HOW MUCH IS WORKING, DOSAGE ESTIMATE AND DRUG SELECTION AND DECISIONS MOVING FORWARD IN CLINICAL TRIALS CAN BE MADE IN AN EFFICIENT WAY. >> THANKS, RANDY. IN ADDITION TO YOUR QUESTION, I'LL ASK ABOUT COMMENTING ON HOW TRANSLATIONAL AND BASIC SCIENCES AND CLINICAL SCIENTISTS COLLABORATE IN BIOMARKER DEVELOPMENT. >> SURE. THANK YOU VERY MUCH. I WOULD LIKE TO DRILL DOWN MORE DEEPLY HOW WE MAKE DECISIONS SO WE KNOW THE (INDISCERNIBLE) CLINICAL TRIAL THE PAST IMMUNIZATION TRIAL FOR MILD TO MODERATE ALZHEIMER'S DISEASE DID NOT MEET ITS END POINTS. I UNDERSTAND YOU KNOW THESE BEAR, I HAVEN'T READ THE BIOMARKER STUDIES RECENTLY, AGAIN, BUT AS I UNDERSTAND THE AMYLOID LOAD WAS REDUCED. SUGGESTING TARGET ENGAGEMENT, CMS WAS CRITICAL ARC BETA BUT THE NEURODEGENERATION BUOY MARKERRER THE CSF TAU EVERYONE ATTRIBUTES TO -- AS -- TO BEING PROXIMAL CAUSE OF DEGENERATION, THAT ALSO WAS NORMALIZED SO THAT CAME DOWN. TWO BIOMARKERS RESPONDED TO DRUG UNFART FAT NATALIE THE PATIENTS DIDN'T RESPOND WITH RESPECT TO MEMORY IMPAIRMENTS. YET, THE COMMUNITY IS GOING FORWARD WITH ANOTHER CLINICAL TRIAL. THE ARGUMENT IS BEING MADE THAT IT'S PREVENTION TRIAL THAT MAY BENEFIT AT THAT EARLIER STAGE, INCLUDING THE NEURODEGENERATION BIOMARKER AND I WOULD ASSUME THAT WOULD LEAD ONE TO MOVE TO SOMETHING ELSE, ANOTHER TARGET SO HELP US UNDERSTAND HOW WE INTERPRET IN A RAIL CLINICAL TRIAL TO DECIDE GO, NO GO FOR ANOTHER SHOT ON GOLD. >> JOHN, THAT'S A CRITICAL POINT HOW TO VALUE DADE BIOMARKERS. SO THERE'S OOH TWO PHASE 3 -- TWO SETS OF PHASE 3 TRIALS COMPLETED WITH TWO DIFFERENT DRUGS. ONE WITH (INDISCERNIBLE) AND THE OTHER WITH (INDISCERNIBLE). THE STORY IS COMPLEX IN THAT THE BABZINUSIMAB STUDY SHOWS SMALL EFFECTS ON CSF PHOSPHOTAU LEVELS. BUT NOT IN OTHER IMAGING -- I'M SORRY, NOT OTHER CSF MEASURES BUT DID SHOW ALSO A SMALL EFFECT ON THE AMYLOID IMAGE -- LESS THAN WHAT WAS IN EARLY EARLIER TRIAL. IN THAT STUDY THERE WAS CLINICAL COGNITIVE DATA SUGGESTED THERE WAS NO TREND TOWARDS COGNITIVE OR CLINICAL BENEFIT. AND STUDIES WITH THAT DRUG HAVE BEEN STOPPED. HOWEVER, IN CONTRAST IN THE (INDISCERNIBLE) TRIAL IN THAT STUDY THERE WAS SIGNIFICANT CHANGES IN CEREBRAL SPINAL FLUID AND BLOOD SOLUBLE LEVELS OF AMYLOID BETA BUT NO CHANGES IN CEREBRAL SPINAL FLUID PHOSPHOTAU AND NO SIGNIFICANT CHANGES IN AMYLOID IMAGING. FOR SOLUBLE ANTI-AMYLOID BETA DRUG. MANY THAT CASE THE DRUG HAS CONTINUED IN ITS CLINICAL TRIALS STARTING A PHASE 3 MILD ALZHEIMER'S DISEASE CLINICAL STAGE AS WELL AS STARTING IN PREVENTION TRIALS. PEOPLE WHO HAVE AMYLOIDOSIS AND DON'T HAVE SYMPTOMS IN THE HCA-4 TRIAL AS WELL AS IN PEOPLE WHO CARRY MUTATION WHOSE ARE ASYMPTOMATIC IN THE (INDISCERNIBLE) TRIAL. SO JUST GETTING TO YOUR POINT, JOHN, HOW DECISIONS ARE MADE. THE MOST IMPORTANT THING FOR PATIENTS IS WHETHER THE DRUG BENEFITS THEIR SYMPTOMS IN ALZHEIMER'S DISEASE, THAT IS COGNITION. IN CRITICAL PERFORMANCE. IT DID SHOW SIGNS OF THAT IN ITS FIRST PHASE 3 TRIAL BUT DIDN'T MEET IN BOTH TRIALS AS PRIMARY END POINT. BUT CERTAINLY WERE SUGGESTIVE OF HAVING A DESIRED EFFECT. IN ADDITION IT HAD CSF BIOMARKERS. SO I THINK THIS INFORMATIVE FOR THE FIELD OF ALZHEIMER'S AND PARKINSON TO THINK ABOUT ARE STATE BIOMARKERS USEFUL? YES, LIKELY VERY USEFUL IN TARGETING INDIVIDUALS WHO WOULD RESPOND TO TREATMENT. TWO, WHAT BIOMARKERRERS WILL PREDICT OR CORRELATE WITH CLINICAL COGNITIVE RESPONSE. IN THE CASE OF (INDISCERNIBLE) IT LOOKS LIKE CEREBRAL SPINAL FLUID IN THE BLOOD BIOMARKER FOR AMYLOID BETA HAVE CORRELATED WITH THE USE OF THAT DRUG. SO THAT MAYBE A POTENTIAL FUTURE BIOMARKER. SO THERE'S OTHER STUDIES FOR AMYLOID BETA, OTHER AGENTS DEVELOPED TAU IMAGING. THESE BIOMARKERS ARE INCORPORATED IN TRIALS IN A WAY JOHN ANSWERS YOUR QUESTION WHICH IS HOW DO WE KNOW HOW PREDICTIVE OR USEFUL BIOMARKERS ARE AND FOR WHAT PURPOSE. >> RANDY, LISA WANTED TO MAKE A COMMENT. I WAS GOING TO LET HER SPEAK A SECOND. >> THANK YOU. I WANTED TO CONNECT THE DOTS OUTCOME MEASURES WHICH TOUCHES ON. YOU RAISE THE ISSUE OF WHEN THERE'S NO SIGNAL FROM BIOMARKER IN TERM OF CLINICAL OUTCOMES, ONE CAN ENVISION THE OPPOSITE. THERE IS EXCELLENT CHANGE IN BIOMARKER BUT NO CHANGE AVOID THE OPPOSITE. A LOT OF CHANGE IN CLINICAL MANIFESTATION BUT NO CHANGE IN BIOMARKER. I THINK HOW WE PROCEED BASED ON BOTH OF THOSE POSSIBILITIES. THE BIOMARKER AND THE CLINICAL CHANGE, PART OF IT IS WHETHER THE PROPER OUTCOME MEASURE IS USED AT ALL. IT'S A STICKY WICKET >> I WAS GOING TO SAY ONE POINT I'LL MAKE HERE IS OFTEN -- I THINK WE TRY TO JUMP TOO QUICKLY WITH BIOMARKERS. WE HAVE BIOMARKERS AND WE WANT TO USE THEM IN TRIALS AND TRY TO USE THE TRIALS OF DRUG TO DETERMINE WHETHER WE HAVE A GOOD-BYE MARKER OR NOT. IF WE WANT BETTER BIOMARKERS WE HAVE TO THINK OF THAT ALMOST SEPARATELY AND WE NEED STUDIES INTENDED TO VALIDATE WHETHER WE HAVE A GOOD-BYE MARKER OR NOT, DOES THIS BIOMARKER CORRELATE TO POTENTIAL OUTCOMES AN DETERMINE FROM THAT WHETHER WE HAVE A GOOD-BYE MARKER THEN APPLY THE BIOMARKER IN THE DRUG DEVELOPMENT DESIGN. OFTEN WE TRY TO JUMP TOO QUICKLY TO THE END WITHOUT THINKING VARIOUS STEPS TO VALIDATE THE BIOMARKER. I WANT TO MAKE SHAH POINT. >> WELL TAKEN POINT. >> I CAN BE BRIEF. >> REALLY BRIEF. >> EXAMPLES OF PPMI AND ADNY SHOULD ANYONE THINK THAT COMES TOGETHER WITHOUT A LOT OF EFFORT, IT'S ABSOLUTELY NOT TRUE. I HAVE BEEN GIVING LECTURES ON PPMI AND ADNY AND PEEP AIL APPROPRIATE ME FROM THE SCHIZOPHRENIA WORLD AND SAY HOW DID YOU EVER GET EVERYONE TO WORK TOGETHER. OUTSIDE THE DOOR AND FOCUS ON A MORE IMPORTANT ISSUE, BETTER SCIENCER BETTER THERAPY FOR PATIENTS. IT'S A TRIBUTE TO OUR COMMUNITY THAT CAN COME TOGETHER AND DO A STUDY LIKE PPMI BY THOSE ARE TWO GREAT EXAMPLES OF RESPONSE TO YOUR QUESTION, ANDREW. >> THANK YOU VERY MUCH FOR THAT, JOHN. SO OBVIOUSLY BIOMARKERS CAN FILL UP THE WHOLE MORNING, IN THE INTEREST OF TIME LET WHAT'S MOVE TO 7. THERE'S A LOT OF INTERESTING WORK THE LAST FEW YEARS REGARDING CLINICAL TRIALS, TO ASSESS LONG TERM EFFICACY AND POTENTIAL FOR DISEASE MODIFICATION. AND I WAS CURIOUS TO SEE IF IN THE CONTEXT OF THE ADAGIO STUDY NET CD WHERE WE REALLY, RESOURCE INTENSIVE STUDIES TO TRY TO IDENTIFY A DISEASE MODIFYING EFFECT. WHAT DO YOU THINK THE OUTCOMES OF THESE TRIALS HAVE MEANT TO US, WHAT DO YOU THINK THE LESSONS WE HAVE LEARNED FROM THEM GOING FORWARD MIGHT BE? WERNER, I WAS HOPING YOU MIGHT TACKLE THIS QUESTION. >> MY MIND SUBJECTIVE PERCEPTION OF THOSE TRIALS IS THAT THE NICELY HE WILL STRAIT THE PROBLEM THAT WE ADDRESS THAT WE HAVE BEEN TOO LAX IN DEFINING TARGET ENGAGEMENT BASIC SCIENCE DATA BEFORE (INAUDIBLE) WAS STARTED WERE SORT OF POOR BUT THERE WAS A LOT OF EFFORT PUT INTO THE TRIAL. SO THIS IS A GOOD ILLUSTRATION WE NEED BETTER WAYS TO DEMONSTRATE UP FRONT BEFORE WE ENGAGE IN THESE EXPENSIVE RESOURCE INTENSIVE LONG TERM TRIALS TARGET ENGAGEMENT, WE HAVE AN AGENT THAT WOULD BE AT THE CORE OF THE PATHOLOGY AND PATHOGENESIS FEEDING INTO THE BIOMARKER DISCUSSION ANY CLINICAL SCORE UNDER 18 MONTHS IN THE CASE OF ADDAGICSO IN A DISEASE PARKINSON'S DISEASE WHICH IS SLOWLY PROGRESSIVE IS JUST NOT A GOOD OUTCOME AND SHOWS US WE NEED TO HAVE MARKERS TO MAKE US SURE WE HAVE THE RIGHT AGENT WITH PROPER TARGET AGENT AND SHORT TERM SMALLER STUDIES THERE IS POTENTIAL BEFORE WE ENGAGE LARGER EFFORTS OF THE TYPE WITH THOUSANDS OF PATIENTS, ET CETERA. >> I HAVE OOH QUESTION FOR CHRIS IF YOU LEERING TO TAKE IT ON. THINKING THE CREATINE STUDY WERE NON-PHYTOLTY WAS DEMONSTRATE BUD THAT LEADS TO A VERY LARGE LONG TRIAL IN A DIFFERENT PATIENT POPULATION TREATED. I WAS PART OF THIS STEERING COMMITTEE. WE WORKED HARD TRYING TO COME UP WITH A GOOD DESIGN. IS THERE A WAY WE CAN TAKE OUR ACCUMULATED INFORMATION AVAILABLE NOW FROM DIFFERENT TRIALS AND DO SIMULATIONS TO AVOID THAT KIND OF A DILEMMA? STEPS YOU CAN SEE IN BETWEEN THAT MIGHT MAKE US MORE PRECISE IN OUR NEXT ENDEAVOR? >> GOOD QUESTION, CARLY. IT'S A DIFFICULT ONE TO ANSWER. MY PERSONAL BIAS IS NOT NECESSARILY THROUGH SIMULATION STUDIES BUT I THINK WE PROBABLY NEED LARGER MORE COMPLEX PHASE 2 STUDIES. I THINK WE TEND TO -- EVEN WITH THE DESIGNS WE HAVE SEEN IN RECENT YEARS, THEY'RE NOT REALLY TEASING OUT HOW LIKELY IT'S GOING TO BE IN PHASE 3. I THINK WE CAN SPEND MORE TIME IN PHASE 2 LOOKING AT WHETHER THERE'S AN EFFECT OR NOT. BECAUSE WHAT WE ALL WANT TO AVOID IS EXPENSIVE PHASE 3 TRIALS THAT TURN UP NEGATIVE. THAT'S THE WORST CASE SITUATION. BUT IT SEEMS LIKE MY PERSONAL EXPERIENCE, EVERYONE WANTS TO GET PHASE 3 QUICKLY BECAUSE EVERYONE IS CONVINCE THAT THE INTERVENTION WORKS. EXPANDING PHASE 2 TRYING TO COME UP WITH BETTER DEFINED CRITERIA FOR PHASE 2, THE OTHER PIECE THAT GETS TO POINT YOU MADE TRYING TO ADDRESS WHAT IS KNOWN, THIS IS A HOT BUTTON ISSUE PARTICULARLY IN THE STATISTICS COMMUNITY IS MORE BASE YEN FRAMEWORK TAKING INTO ACCOUNT PRIORS AND ADDRESSING WHAT IS NOBODY, PRIOR INFORMATION FROM PREVIOUS STUDIES. WHAT WE HAVE SEEN IN RECENT YEARS IS BAYESIAN METHODS IN EARLY PHASE CLINICAL TRIALS. THERE IS HESITANCY IN LATER PHASE TRIALS BECAUSE THERE'S DISAGREEMENT HOW STRONG PRIOR INFORMATION IS, WHAT WEIGHT TO PUT ON PRIOR INFORMATION. THOSE WEIGHTS CAN'T INFLUENCE THE POSTERIOR DISTRIBUTIONS YOU GET AT THE END. SO NOT CLEAR HOW TO MAKE THE ASSUMPTIONS AN AT THE BEGINNING, I THINK THERE'S PROMISE THERE, I THINK THERE'S SOME OPERATIONAL ISSUES RELATED THAT HAVE TO BE ADDRESSED TO USE THAT BUT IT IS LOGICAL YOU WOULD LIKE TO USE, PARTICULARLY IF WE TAKE THE FIRST RECOMMENDATION, LARGER MORE COMPLEX PHASE 2 STUDYS WE DON'T WANT TO START OVER AND IT SEEMS INEFFICIENT BUT WE DON'T WANT TO HEAVILY BIAS THE END OF THE PHASE 3 TRIAL BASED ON WHAT WE PREDICT AT THE END SO IF THERE'S A COMPROMISE WAY TO ADDRESS THOSE, THAT WOULD BE WHERE IT WOULD BE HELPFUL TO SEE THE FIELD GO IN THE FUTURE. >> SMALL FOLLOW-UP OR IMPORTANT POINT FOLLOWING UP ON THE POINT OFTEN WE DON'T HAVE A LOT OF INFORMATION ABOUT WHAT REALLY IS GOING TO BE THE EFFECT OF THE ENTERSECTION. IN TERMS OF CLINICAL TRIAL DESIGN WE ARE FORCED TO PRIMARY OUTL COME MEASURES. WHERE THESE TWO THINGS REALLY DEFINE EACH OTHER. WE DON'T HAVE ENOUGH INFORMATION AND WE END UP HAVING TO FOCUS ON SOMETHING THAT CAN POTENTIALLY TUNE THE SUCCESS OF THE PROJECT, IT'S A CLINICAL TRIAL POTHOLE. >> WE'RE RUNNING OUT OF TIME A LITTLE BIT. I WANT TO TOUCH ON RECOMMENDATION TEN BEFORE WE DID. CHRIS I WAS GOING TO ASK YOU TO COMMENT ON THIS RECOMMENDATION A LITTLE BIT. BIG DATA, SOMETHING LIKE THAT. HOW CAN WE TAKE ADVANTAGE OF THINGS LIKE LARGE GENETIC DATABASE REPOSITORIES, SOCIAL MEDIA OR SIMPLER THINGS. THE ADNE DATA TO DESIGN BETTER TRIALS. >> BIG DATA IS POTENTIALLY ADVANTAGEOUS AND SCARY. THAT'S WHAT WAS BEING ADDRESSED IN THAT ARTICLE. BIG DATA FULL OF HOLES AN MISSING DATA WAS NOT COLLECTED IN A VERY EFFICIENT MAPPER IS NOT THAT HELPFUL. IF YOU HAVE LARGE DATA SETS, IT'S REALLY IMPORTANT INFORMATION. I ALSO THINK YOU NEED TO HAVE, BACK TO THIS COLLABORATION. YOU NEED TO HAVE THE INFORMATICS INDIVIDUALS DOING THE BIG DATA, YOU NEEDNE CLINICS, STATISTICIANS, WHAT ARE REASONABLE THINGS TO TRY TO ADDRESS IN BIG DATA. WHAT IS NOT GOING TO BENEFIT RUN INFINITE NUMBERS OF ANALYSIS AND SEE WHAT COMES OUT OF IT AND TRY TO JUSTIFY FINDINGS WE HAVE. WE GET A LOT OF TYPE ONE ERRORS, THINGS THAT ARE RANDOM CHANCE THAT ARE HARD TO DIFFERENTIATE. SO I THINK EVEN WITH THE INFORMATICS CAPABILITIES IT WILL BE IMPORTANT TO HAVE GROUPS THINKING ABOUT WHAT SHOULD BE LOOKED AT FROM A BIG DATA PERSPECTIVE, TIEING THAT WITH CLINICAL INFORMATION, THOUGH YOU CAN LEARN THINGS BUT THE OTHER SIDE IS TO NOT OVERINTERPRET THINGS OUT OF THAT. ALMOST ANYTHING IN MY MIND FROM THESE LARGE DATA SETS IS HYPOTHESIS GENERATING SO THINGS THAT COME OUT NEED TO BE REPLICATED IN A SENSE BEFORE WE REALLY IN MY MIND PUT CREDENCE IN TERMS OF WHERE IT COMES FROM. SO THE POINT I MADE IN MY PRESENTATION, I THINK WHAT I WAS TALKING TRIAL DESIGN, IT'S TRUE HERE AS WELL, YOU NEED VARIOUS FIELDS HOW DO WE INTERPRET THIS, TRYING TO INTERPRET THIS, DOING TRIAL DESIGN AND CLINICS TRYING TO TAKE THE BEST AND PLUG IN BUT GROUPS COMMUNICATING TOGETHER TO TRY TO DO IT MORE EFFICIENTLY. >> WE HAVE TIME FOR ONE QUESTION. >> HELLO (INAUDIBLE) PATIENT. YOU MENTIONED THAT 30% OF ALZHEIMER'S PATIENTS WERE FOUND TO NOT HAVE ALZHEIMERS IN WHATEVER CLINICAL STUDIES. I WONDER IF THAT IS POSSIBLE WITH PARKINSON'S AND WHAT THE POSSIBLE PERCENTAGE MIGHT BE. >> SO WE HAVE FOUND SIMILAR NOT AS DRAMATIC CHANGES IN PEOPLE WITH PARKINSON'S TRIALS USING IMAMMING STUDIES LOOKING AT THE DOPAMINE TRANSPORTER, YOU CAN SEE A NUMBER OF PEOPLE ENROLLED IN EARLY PHASE TRIAL DON'T SHOW ANY CHANGES ON THAT PARTICULAR TASK SO WOULD SUGGEST THEY HAVE OTHER PROBLEM NOT WHAT WE THINK OF AS PARKINSON DISEASE, IT TENDS TO BE LOWER THAN ALZHEIMER'S, MAYBE 15% IN THE EARLY PHASE OF DISEASE. SO JUST AROUND THE TIME OF DIAGNOSIS, IF YOU WAIT LITTLE BIT LONGER OFTEN IT BECOMES MORE CLEAR THAT THE CLINICAL DIAGNOSIS IS NOT CORRECT. SO MAYBE LOWER THAN P LOOKING AT SOMEONE JUST BEGINNING THERAPY WITH A DOPAMINERGIC AGENT. >> THANKS FOR THAT QUESTION. ONE LAST. >> A FOLLOW-UP ON THAT. JEFF (INAUDIBLE) THE UDALL CENTERS HAVE INITIATED AN AUTOPSY STUDY ASSOCIATION STUDY AND IN OUR STUDY 25% OF CASES TURN OUT NOT TO HAVE LOUIS BODY PARKINSON DISEASE. OTHER PANEL LOATHIC HAVE SHOWN THE NUMBERS FAIRLY HIGH. I WAS WONDERING HOW THAT PROBLEM IS GOING TO AFFECT CLINICAL TRIALS BECAUSE IT WAS MENTIONED AS ALZHEIMER'S BUT CLEARLY A BIG PART OF PARKINSON'S AS WELL. >> EXCELLENT POINT. IN THE INTEREST OF TIME WE'LL TACKLE CLINICAL HETEROGENEITY IN ONE OF LATTER TWO PANELS, IT WAS AN IMPORTANT THEME OUR GROUP RETURN TO AGAIN AN AGAIN. I THINK IT'S TIME FOR A BREAK NOW. WE'LL COME BACK IN A HALF HOUR. THE NEXT SESSION IS OPPORTUNITIES TO IMPROVE OUTCOME MEASURE AND PD RESEARCH WITH PRESENTATION BY DR. LISA SHULMAN. >> HOW DO I MOVE THINGS FORWARD HERE. GOOD MORNING. I WANT TO THANK ALL THE ORGANIZERS FOR THE PRIVILEGE OF PRESENTING AT THIS IMPORTANT MEETING. WE HEARD EXTRAORDINARILY IMPORTANT RECOMMENDATIONS, BOTH SYMPTOMATIC TREATMENT AREA AND DESIGN OF CLINICAL TRIALS. II WANT THE TO MAKE THE IMPORTANT POINT THE QUALITY OF ALL THIS RESEARCH WILL BE LIMITED BY THE QUALITY OF OUTCOME MEASURES THAT WE APPLY. P AND THIS WAY OUTCOME MEASURES ARE A COMMON DENOMINATOR THAT RESULTS IN LIMITATIONS ACROSS ALL OF CLINICAL RESEARCH. THE FACT IS MEASURES HAVE NOT KEPT PACE WITH OUR EXPANDED UNDERSTANDING OF PD DIVERSE MANIFESTATIONS. FORTUNATELY, MODERN MEASUREMENT PRINCIPLES AND IT TECHNOLOGY PROVIDE NEW OPPORTUNITIES TO IMPROVE SENSITIVITY, PRECISION, AND PRACTICALITY OF OUR MEASURES. THE UPDRS HAS BEEN A VERY IMPORTANT WORKHORSE AS OUTCOME MEASURE FOR DECADES NOW. BUT FACT IS, WE NEED TO BE LOOKING FURTHER TO IDENTIFY OPTIMUM OUTCOME MEASURES IN CLINICAL TRIALS FOR PARKINSON'S DISEASE. THERE'S OPTIONS NOT ADEQUATELY UTILIZED. AMONG ARE PATIENT REPORTED OUTCOME MEASURES. OTHER TYPES OF CLINICIAN REPORTED OUTCOME MEASURES, PHYSICAL AND COGNITIVE PERFORMANCE MEASURES WHICH INTERESTINGLY HAVE BEEN RELATIVELY UNCOMMONLY USED IN CLINICAL TRIALS. TIME GATE SPEED, DUAL TASK PERFORMANCE AND SIMULATIONS OF ADL PERFORMANCE. ALSO SYMPTOM CLUSTER MEASURES. AND COMPOSITE OUTCOMES WHICH WAS APPLIED IN THE OS 1 STUDY. SO HOW DO WE LEARN ABOUT THIS? WE NEED TO APPLY ADVANCES IN MEASUREMENT SCIENCE TO PARKINSON DISEASE. THE NIH IS COMMENDED ALONG WITH THE HUNDRED DOLLARS FOR SOME VERY IMPORTANT INITIATIVES IN THIS AREA, INCLUDING PROMISE THE PATIENT REPORTED OUTCOMES MEASUREMENT INFORMATION SYSTEM, NEUROQUAL, THE NIH TOOLBOX I'LL TELL YOU ABOUT THOSE THREE A LITTLE BIT. AND THE NIH COMMON DATA ELEMENT YOU HEARD ABOUT. THERE'S ADVANCES IN TECHNOLOGY THAT NEED TO BE BETTER APPLIED. THESE INCLUDE ELECTRONIC MEDDLECAL RECORD, REMOTE ASSESSMENT AND COMPUTERIZED ADAPTIVE TESTING. THESE THREE PROJECTS PROMISE, NEUROQUAL AND NIH TOOLBOX CREATE STATE OF THE SCIENCE ASSESSMENT SYSTEMS. I DON'T WANT TO FORGET TO SAY BY COINCIDENCE TOMORROW IF YOU ARE AROUND, THERE IS ON CAMPUS HERE AT THE NIH, A WHOLE PROGRAM INTRODUCING THESE THREE PROJECTS AND AN AFTERNOON WITH THE TRAINING WORKSHOP. SO WHAT MAKES THEM SPECIAL? THE ITEM, MEASURES ARE MORE PRECISE, EFFICIENT, AND RESPONSIVE. THEY WERE DEVELOPED BY RESPONSE THEORY. PROMISE AND NEUROQUAL ARE ALL PATIENT REPORTED OUTCOME MEASURES. TOOLBOX IS A MAJORITY PERFORMANCE MEASURES BY ALSO HAS EMOTIONAL MEASURE COMPONENTS. ONE KEY PARTS OF THIS IS THAT THEY USE A STANDARD METRIC, A T SCORE WITH MEAN OF 50 AND STANDARD DEVIATION OF 10. ASTONISHINGLY 40,000 PEOPLE HAVE BEEN TESTED IN VALIDATION OF THESE MEASURES. THERE ARE DIVERSE DOMAINS AND DIVERSE FORMATS. THESE FORMATS INCLUDE COMPUTERIZED ADAPTIVE TEST I WILL SAY A BIT MORE ABOUT. SHORT FORMS 8 TO 10 ITEMS IN EACH DOMAIN AND INTERESTING PROMISE HEALTH PROFILE, WITH JUST 29 ITEMS YOU CAN GENERATE SCORES ON DIVERSE DOMAINS ON PROGRESSION, FATIGUE PHYSICAL AND SOCIAL FUNCTION. ONE WAY WHICH THESE NEW TYPES OF MEASURES ACHIEVE BETTER PERFORMANCE IS THAT THE ITEM BANKS AND HERE YOU SEE AN EXAMPLE OF THE PHYSICAL FUNCTIONING EYE TESTIMONY BANK IN PROMISE, INCLUDES ITEMS THAT COVER THE ENTIRE RANGE OR MUCH OF THE RANGE MORE RANGE THAN CUSTOMARILY APPLIED, OF PHYSICAL FUNCTION, INCLUDING ITEMS FOR PEOPLE WHO ARE BED BOUND, ARE YOU ABLE TO GET IN AND OUT OF BED, TO PEOPLE HIGH FUNCTIONING, ARE YOU ABLE TO RUN SEVERAL MILES. THE RESULT OF INCLUDING ITEMS THAT HAVE A FULL RANGE LIKE THIS IS REDUCED FLOOR AND CREAMING EFFECTS. THIS IS -- CEILING EFFECTS. THIS IS REPRESENTED IN THIS PARTICULAR STUDY COMPARING THE STROKE IMPACT SCALE WHICH IS ON YOUR LEFT, TO RESULTS WITH THE PROMISE PHYSICAL FUNCTIONING SCORE ON YOUR RIGHT. WHAT YOU CAN SEE ON THIS SAME COHORT IS A VERY LARGE PROPORTION OF STROKE PATIENTS SCORED 100. 20% SCORED 100 WHICH WAS VERY LOW IMPAIRMENT. WHEREAS ON THE PROMISE MEASURE YOU HAVE A NORMAL DISTRIBUTION BECAUSE OF THE FACT THAT THE ITEMS ARE MORE REPRESENTATIVE OF A FULL RANGE. AMAZINGLY, THE PATIENT BURDENNEN WAS LESS IN THE PROMISE MEASURE THAN IN THE STROKE MEASURE BECAUSE COMPUTERIZED ADAPTIVE TESTING ONLY FOUR ITEMS COMPLETED ON THE PROMISE SHE SURE, 16 STROKE MEASURE. SO A COMPUTERIZED ADAPTIVE TESTING WHAT THE CAT DOES IS IT SUCCESSIVELY SELECTS QUESTIONS TO MAXIMIZE PRECISION ON WHAT IS KNOWN ABOUT THE EXAMINEE FROM PREVIOUS QUESTIONS. IF YOU COMPLETE QUESTION 1, NEUTRAL QUESTION BASED ON RESPONSE TO QUESTION ONE, A SPECIFIC FOLLOW-UP QUESTION IS CHOSE OPINION SURROUNDING WHAT THE RESPONSE WAS TO THE FIRST QUESTION AND THEN IN THE THIRD QUESTION TO KEEP GETTING CLOSER IN PRECISION, AND MAINTAINING A WIDE RANGE. SO IT DEPENDS ON WHAT THAT FIRST ANSWER WAS, BASED ON LOW OR HIGH FUNCTION THEN FORWARD FROM THERE. FROM BECAUSE OF THE PRESENCE OF T SCORES, IN ORDER THE SAME METRIC BEING USED ACROSS ALL THESE DOMAINS, ANOTHER IMPORTANT ADVANTAGE IS COMPARABILITY, COMPARING DIFFERENT DOMAINS IN A SINGLE CONDITION LIKE PARKINSON'S DISEASE. HERE YOU CAN SEE ON THIS WRINKLE COLOR GRAPH WHERE THE RED ORANGE AREA IS FUNCTION AND BLUE AREA IS BETTER FUNCTION. THEN ON THE LEFT-HAND SIDE IS A WHOLE BUNCH OF DOMAINS THAT WERE APPLIED. ANGER, ANXIETY, DEPRESSION, FATIGUE, PAIN, PHYSICAL FUNCTION AND SOCIAL FUNCTION. AT A GLANCE YOU CAN SEE THIS INDIVIDUAL IS HAVING MORE PROBLEMS WITH YELLOW BAR ANXIETY, DEPRESSION, PHYSICAL FUNCTION, AND NO PROBLEMS AT ALL IN FATIGUE. NEUROQUAL AND PROMISE ARE VERY CLOSE COUSINS TO EACH OTHER. THERE ARE A LOT OF OVERLAP BETWEEN THESE TWO PROJECTS. PROMISES THE LARGER, BUT VALIDATE AID CROSS ALL MEDICAL POPULATIONS. NEUROQUAL FOCUSED ON NEUROLOGIC POPULATIONS. SO THE IMPORTANT POINT HERE IS THE OPPORTUNITY THAT THESE PROJECTS AFFORD US TO UTILIZE HIGHER QUALITY MORE PRECISE MORE RESPONSIVE MEASURES. THE NIH TOOLBOX WAS DEVELOPED TO ASSESS SO CALLED HEALTHY AGING. THIS ENCOMPASSES BRIEF COMPREHENSIVE ASSESSMENTS AND IMPORTANTLY THOUGH WE'RE TALKING PARKINSON'S DISEASE, THE NIH TOOLBOX WEBSITE HAS DATA THAT IS IN THE PUBLIC DOMAIN, ACCESS IT ON PERFORMANCE ACROSS DIVERSE DEMOGRAPHIC GROUPS. AMONG SAY THE ENTIRE AGE RANGE PERFORMANCE ON THE VARIOUS MEASURES THAT THEY HAVE ON THEIR WEBSITE. MOTOR COGNITION AND SENSATION AND THE EXAMPLE I WANTED TO MAKE WAS THE MOTOR DOMAIN FRAMEWORK WHICH INCLUDES THE SUBDOMAINS. WHAT YOU FIND ON THE WEBSITE ARE WELL VALIDATED PERFORMANCE MEASURES WITH ALL THE DATA BY DEMOGRAPHIC GROUPS THAT I DESCRIBED. THIS WOULD BE QUITE HELPFUL TO PLAN A TRIAL IN PARKINSON'S DISEASE. A REALLY IMPORTANT VITAL AREA WE NEED TO MOVE FURTHER ON IS IDENTIFYING CLINICALLY IMPORTANT DIFFERENCES ON ALL THE OUT MEASURES IN PARKINSON'S DISEASE. AT THE HEART CLINICALLY IMPORTANT DIFFERENCE IS LINKING THE EFFICACY OUTCOME TO WHAT IS A MEANINGFUL CHANGE. WHAT IS A MEANINGFUL DIFFERENCE. NOT JUST THE STATISTICAL DIFFERENCE. SO AS AN EXAMPLE IN THIS GRAPH, THIS IS AN EMPHYSEMA POPULATION. WE SEE IN THE UPPER LINE ON THE GRAPH, THIS IS A TRIAL WHERE THE INTERVENTION GROUP RECEIVED LUNG VOLUME REDUCTION SURGERY. THE CONTROL GROUP DID NOT RECEIVE SURGERY. >> BASELINE THE ASTERISK SHOWING THAT THERE IS A STATISTICAL DIFFERENCE BETWEEN THE CONTROL GROUP AND INTERVENTION GROUP. THE GRAY BAR SHOWS YOU THE CLINICALLY IMPORTANT DIFFERENCE ON THIS SCALE WHICH IS .5. SO BY HAVING THE CLINICALLY IMPORTANT DIFFERENCE WE ARE ABLE TO IDENTIFY THIS IS NOT JUST A STATISTICAL DIFFERENCE BUT IS IN FACT EXTREMELY LARGE CLINICALLY IMPORTANT DIFFERENCE. ANOTHER IMPORTANT AVENUE FOR FUTURE STUDY, ESPECIALLY WITH TECHNOLOGY ADVANCING, IS TO UNDERSTAND WHETHER DIFFERENT MODES OF ADMINISTRATION RESULT IN DIFFERENCES IN RESPONSE. AND PROMISE THE PROMISE PROJECT HAS PERFORMED STUDIES IN THIS AREA, AND HAVE SHOWN IN GENERAL MEDICAL CONDITIONS THAT THERE WAS NO DIFFERENCE BETWEEN PEOPLE WHO TOOK MEASURESES WITH PAPER AND PENCIL OR DESKTOP iPHONE OR iPAD. PARKINSON'S DISEASES REMAIN ASCII OPEN QUESTION, WOULD WE SEE EQUIVALENCY IN TERMS OF PATIENT ABILITY TO MANAGE DATA ENTRY IN EACH OF THESE WAYS, INTERESTING WE HAVE STARTED IN CLINICAL TRIALS TO UTILIZE SOME OF THIS TECHNOLOGY BUT THIS HAS NOT BEEN REALLY ADEQUATELY DEMONSTRATED. THE ELECTRONIC MEDICAL RECORD IS ANOTHER OPPORTUNITY FOR THE FUTURE IN TERMS OF RESEARCH. TO ALLOW US TO INTEGRATE OUTCOME MEASURES TO THE ELECTRONIC MEDICAL RECORD. WHEN WE BEGIN TO INTEGRATE TYPE OF OUTCOME MEASURE, PATIENT REPORTED MEASURES CLINIC REPORTED MEASURES INTO THE EMR. WE ARE ABLE TO PROMOTE A NEW TYPE OF RESEARCH, ADVANCE QUALITY OF CARE, AT THE SAME TIME MEET A VARIETY OF REGULATORY MANDATES. ANOTHER OBSTACLE IN TERMS OF CLINICAL TRIALS IN GENERAL HAS ALWAYS BEEN THAT PARKINSON'S DISEASE SPECIALISTS PERFORMING CLINICAL TRIALS ARE NOT GEOGRAPHICALLY WELL DISTRIBUTED THROUGHOUT OUR COUNTRY. HERE IS AN EXAMPLE THROUGH MY OWN STATE OF MARYLAND. THE NEXT SLIDE I WANT TO THANK RAY DOOR I FOR, THIS SHOWS HOW THREE COUNTIES OUT OF 23 IN MARCH MARE HAVE ANY PARKINSON'S DISEASE SPECIALISTS. WE SEE A SIMILAR MAP ELSEWHERE. SO AGAIN TECHNOLOGY GIVES US AN OPPORTUNITY THE IMPROVE ACCESS FOR SPECIALTY CARE AND CLINICAL TRIALS. THE POTENTIAL BENEFITS OF REMOTE ASSESSMENT IN TRIALS ARE MANY INCLUDE REGULAR DEUCED COST, POTENTIALLY SAVING TIME AND RECRUITMENT, REDUCING NUMBER OF IN PERSON VISITS. FACILITATING RECRUITMENT, ACCESSING PATIENT WHOSE NEVER WOULD HAVE BEEN ABLE TO PARTICIPATE IN TRIALS BECAUSE OF TRAVEL BURDEN. IMPROVING DATA COLLECTION BY COLLECTING DATA REAL TIME REDUCING THE NEED FOR SUBJECTIVE DIARIES AND CAPTURING DATA DIRECTLY INTO ELECTRONIC DATABASES. I'M GOING TO MAKE -- CHANGE GEARS HERE FROM THE FIRST RECOMMENDATION OF THE OUTCOMES GROUP TO OUR SECOND RECOMMENDATION WHICH FOCUSES ON MINORITY PARTICIPATION AN CLINICAL RESEARCH. FRINGEICALLY IT HAS NOT LIVED UP TO OUR EXPECTATIONS. WE NEEDY VERSE SUBJECTS TO COLLECT DATA WITH BROAD APPLICATION. EVIDENCE SUGGESTS DISPARITIES OF PREVALENCE AND NATURAL HISTORY PARKINSON'S DISEASE ARE PRESENT. MINORITIES CANNED FOR ONE-THIRD OF THE AMERICAN POPULATION BUT LESS THAN 1/10 OF CLINICAL TRIAL PARTICIPANTS. A PUBMED SEARCH SHOWED OUT OF 17% PD TRIALS OVER THE PAST 20 YEARS THAT REPORTED RACIAL PARTICIPATION, ONLY 8% OF THE SUBJECTS WERE NON-WHITE. THERE HAVE BEEN ATTEMPTS TO INCREASE PD PARTICIPANT DIVERSITY BUT THEY HAVE BEEN UNSUCCESSFUL. BARBARA TILLEY IS IN THE AUDIENCE TODAY AND SHE KNOWS WELL BECAUSE SHE SPEARHEADED THE LS-1 ANCILLARY TRIAL TO INCREASE DIVERSITY, THAT WAS STOPPED EARLY FOR LACK OF EFFICACY. A HOST POST HOCK ANALYSIS SHOWS HIGH END ROLLERS OF DIVERSE SUBJECTS DID BETTER WITH COMMUNITY OUTREACH. LOW ENROLLERS PLACED GREATER RESPONSIBILITY FOR LOW ENROLLMENT ON PERSPECTIVE PARTICIPANTS. SO NEW APPROACHES ARE NEEDED TO UNDERSTAND THE BARRIERS AND DEVELOP NOVEL APPROACHES. IT'S LIKELY COMMUNITY BASED RESEARCH INITIATIVES WILL BE NECESSARY AND TO BE FRANK VERY FEW PARKINSON'S CLINICAL TRIALISTS HAVE EXPERTISE IN THIS AREA. SO WITH THAT, I WANT TO REMIND YOU WHAT THE TWO TOP RECOMMENDATIONS FROM THE OUTCOMES GROUP WERE AND WE CAN COMMENCE OUR PANEL. THANK YOU. >> THANK YOU, LISA, FOR THAT TERRIFIC PRESENTATION, IT REALLY SUMMARIZED THE AREA WELL AND WAS A PLEASURE TO LISTEN TO. AS YOU CAN SEE WE HAVE TWO RECOMMENDATIONS FROM THE -- IN THE OUTCOMES AREA. IF YOU -- OBVIOUSLY YOU NOTICE ONE IS RANKED NINE AND ONE IS RANKD 11. SO THEY DIDN'T -- THEY WEREN'T AMONG OUR TOP-RATED RECOMMENDATIONS. BUT I THINK THERE WAS GENERAL CONSENSUS AMONG THE GROUP THAT THOUGH AS STANDALONE RECOMMENDATIONS THEY WEREN'T RANKED HIGH THAT THEY WERE IMPORTANT -- COULD BE IMPORTANT COMPONENTS ALMOST EVERY OTHER INITIATIVE WE TALK ABOUT. SO CLINICAL TRIAL INITIATIVES PRODROMAL PD, YOU NAME IT, NEED FOR OUTCOME MEASURES FOR MORE DIVERSE PARTICIPATION IN PD RESEARCH, IS A BROAD NEED THAT COULD BE INCORPORATED INTO HIGH -- SOME MORE HIGH PRIORITY SCIENTIFIC AREAS IDENTIFIED IN HIGHER RANKED PRIORITIES. SO I WANT TO START THE SESSION BY A QUESTION THAT CAME UP EARLIER, WHICH IS JOHN ASKED, WHAT'S IMPORTANT TO PATIENTS, AND ARE WE CAPTURING THE THINGS THAT ARE MEAN -- CLINICALLY MEANINGFUL TO PATIENTS IN CLINICAL TRIALS? I KNOW LISA AND WERNER BOTH HAD THOUGHTS ABOUT THAT. WHEN THE QUESTION CAME UP AND WE DIDN'T FULLY ANSWER IT. LISA WONDER IF YOU CAN TACKLE THAT. >> PART OF THE PROCESS OF DEVELOPING OR MEASURING CLINICALLY IMPORTANT DIFFERENCE, IS YOU SHOULD INCLUDE PATIENT REPORTED OUTCOMES IN THE CLINICALLY IMPORTANT DIFFERENCE TO IN FACT BE ABLE TO DEMONSTRATE THIS IS MEANINGFUL TO PATIENTS. SO THERE IS NO QUESTION THAT WE NEED TO BE USING PATIENT REPORTED OUTCOME MEASURES FOR THIS PURPOSE. AND ALSO APPLY THE CLINICALLY IMPORTANT DIFFERENCES, THESE ARE TWO WAYS WE CAN BRING PATIENTS INTO THE THINKING. THE MPRS DOES NOT HAVE A PATIENT REPORTED OUTCOME MEASURE. IT IS AN INTERVIEW DEVICE, NOT A PATIENT REPORTED OUTCOME MEASURE. SO WE HAVE A LONG WAY TO GO TO IMPROVE PATIENT CENTEREDNESS OF OUR RESEARCH. >> THANKS. Q. LORI I WANT TO ASK YOU A QUESTION RELEVANT TO RECOMMENDATION NUMBER 9. I'M INTERESTED IN THE IDEA OF LEVERAGING TECHNOLOGY FOR OUTCOME MEASURES BUT ALSO MORE IMPORTANTLY HOW DO WE BRIDGE OUTCOME MEASURES ACROSS TRANSLATIONAL DIVIDE? HOW CAN WE DEVELOP CLINICAL OUTCOME MEASURES THAT CAN BE RELEVANT P TO ANIMAL MODELS TO INCREASE PREDICTIVENESS OF THE PRE-CLINICAL STUDIES IN CLINICAL STUDIES? >> I THINK STARTING OFF FROM THE PATIENT OUTCOME SIDE, USING OPPORTUNITIES AND TECHNOLOGIES THE OTHER SIDE OF THE COIN THAT LISA WAS ALLUDING TO PATIENT REPORTED OUTCOMES, THERE ARE THINGS PATIENTS CAN REPORT EASILY VERY RELIABLY FALLING OR FREEZING BEING AN EXAMPLE AND PHYSICIAN MEMBERRING THIS UP BECAUSE IT'S A FLUCTUATING PHENOMENON. SO I THINK THIS IS WHERE THERE IS ONE AREA WHERE TECHNOLOGY WITH SMALL SHAPES THAT WOULD RECORD OVER PERIODS OF WEEKS WHICH TECHNOLOGY IS AVAILABLE, MOVEMENT PARAMETERS INCLUDING GATE PARAMETERS INCLUDING TURNING THE BED, ET CETERA, COULD BE USED. TO WHAT EXTENT YOU CAN USE THAT AND BRIDGE ANIMAL MODELS I SUPPOSE YOU COULD TAKING USING TECHNOLOGIES AS BEHAVIORAL READ OUTS IN ANIMAL MODELING AND LEARN FROM THERE AND FORM THAT BRIDGE YOU'RE ALLUDING TO. OTHER AREAS FOR CLINICAL TRIALS USING IT SOLUTIONS TO RECORD OUTCOMES THAT INCLUDE NOT ONLY ON OFF DIARIES WE STRUGGLE WITH, BUT ALSO ORTHO STATIC HYPERTENSION WHICH IS A MAJOR NON-MOBILE PROBLEM WE'RE DEALING WITH, AND INTERVENTIONS ON THAT. OTHER THAN ASKING PATIENTS DID THEY OR DID THEY NOT HAVE SYNCOPE. SO THERE IS -- THERE ARE OPPORTUNITIES WHICH NEED TO USE MORE OFTEN TO GET MORE RELIABLE OUTCOMES IN SOME OF OUR PROBLEMS. >> THANKS. CAR LEE, I WANT TO ASK YOU A QUESTION ABOUT REMOTE FOLLOW-UP. YOU HAVE BEEN TRYING TO FOLLOW PATIENTS WHO PARTICIPATE PREVIOUSLY IN CLINICAL TRIALS FOR LONG TERM OUTCOMES. WHERE ARE OPPORTUNITIES YOU SEE FOR LONG TERM FOLLOW-UP CLINICAL TRIAL COHORTS AND HOW IMPROVED OUTCOME MEASURES OR EMERGING INFORMATION TECHNOLOGIES, HELP WITH THAT. >> ONE OF THE EASIEST WAYS TO BE ABLE TO HAVE THIS LIFE LONG OBSERVATION OF PARKINSON'S DISEASE SO IMPORTANT TO THE QUESTIONS WE HAVE ASKED SO FAR, THIS MORNING IS TO TAKE ADVANTAGE OF PEOPLE WHO HAVE BEENEN ROLLED AND WELL CHARACTERED IN CRIMINAL CLINICAL STUDIES BE THEY TRIALS POPULATIONS OR OTHER KINDS OF CAREFULLY -- CHARACTERIZED GROUPS OF PATIENTS AND THE PROBLEM OF COURSE IS THAT AT A CERTAIN POINT PEOPLE BECOME DISABLED, THEY MOVE, THINGS HAPPEN AND YOU LOSE PEOPLE. AND YOUR POPULATION WITH ALL BEST INTENTIONS BECOMES INCREASINGLY SMALL. AND SOMETIMES THE SIZE OF THE POPULATION IS NOT THE ONLY PROBLEM, IT'S THAT THE HEALTHIER PEOPLE ARE ONES YOU'RE FOLLOWING AND ONES YOU CARE MOST WHO DEVELOP ADVERSE OUTCOMES OF PARKINSON'S ARE ONES YOU HAVE LOST. SO WE DEVELOPED WAYS TO ADDRESS THIS, SOME AS SIMPLE AS CALLING PEOPLE ON THE PHONE, QUESTIONNAIRES HAVING SENT BACK INFORMATION IDENTIFYING A SECOND INFORMANT SO IF THE PERSON BECOMES DISABLED YOU CAN STILL BE IN TOUCH WITH INFORMANT. A NEW WAY TO TRY TO ADDRESS THIS WHICH CAN GIVE AN EVEN HIGHER QUALITY OF INFORMATION IS USING TELEMEDICINE. WHERE YOU CAN USE NEW COMPUTER TECHNOLOGY TO ACTUALLY LOOK AT SOMEONE SAY YOU'RE DOING A POP STUDY AND YOU WANT TO LOOK AT PEOPLE IN AN AREA WHERE THERE AREN'T SPECIALISTS, YOU CAN EXAMINE AND VALUE WAIT DIAGNOSIS O -- EVALUATE PARKINSON'S TELEMEDICINE AND FOLLOW PROSPECTIVELY. IF YOU WANT TO LOOK FORWARD TO SEE HOW PEOPLE CHANGE OVER TIME, LOOK AT THE LATE DISEASE CONSEQUENCES. THESE ARE REALLY CRITICAL KNEW NEW APPROACHES AND TECHNOLOGIES. PARTICIPATION IN CLINICAL TRIALS, PEOPLE WHO LIVE IN PARTS OF THE COUNTRY WHERE THERE AREN'T MOVEMENT DISORDER SPECIALISTS OR UNIVERSITIES COULD BE INVOLVED BY SOME OF THESE REMOTE FOLLOW-UP METHODS AS WELL. >> THANKS. THERE ARE GREAT OPPORTUNITIES FOR TELEMEDICINE TO THE REACH PEOPLE AND TO ALLOW FOR LONG TERM FOLLOW-UP IS REALLY IMPORTANT. I WANT THE ASK ANOTHER QUESTION ABOUT USING THE YOU COME MEASURES INTRODUCED IN THE TOOLBOX. SPECIFICALLY PARKINSON'S PATIENTS. READY TO GO IN PARKINSON'S TRIALS. AND FOLLOW-UP TO THAT I WANT THE ASK YOU, THEY LEND MORE PRECISION MAYBE BETTER PSYCHOMETRIC PROBLEMS IN TERMS OF CEILING EFFECT YOU SHOW THAT IN SLIDES. ARE THERE OTHER WAYS THESE ARE BETTER MAYBE GIVE ADDED VALUE EXISTING MEASURE? >> ONE OF THE STORY THERE IS OFTENTIMES A DIFFERENCE BETWEEN OBJECTIVE CHANGE AND PERCEIVED CHANGE. MY COMMENTS ARE NOT TO SAY PATIENT REPORTED OUTCOME MEASURES ARE BEAR THAN OTHER MEASURE BY NO MEANS, IT'S ONE PIECE OF A LARGER STORY. AND THE PERFORMANCE MEASUREMENTS, COGNITIVE PERFORMANCE MEASUREMENTS IS REALLY AN OPPORTUNITY TO GENERATE IMPORTANT INFORMATION ABOUT QUANTITATIVE CHANGE IN TERMS OF MOBILITY. IT'S KEY. >> UNDERSTANDING THIS BECAUSE FOR SO LONG WE RELIED ON ONE OR TWO ITEMSES ON -- IN TERMS OF HOW SOMEBODY IS WALKING. AND WHAT THE PRESENT PERCEPTION IS WALKING BUT ACTUAL UNDERSTANDING OF THE NORMS QUOTE UP QUOTE IN PD OVER TIME FOR SAY GATE SPEED TESTING OR DISABILITY CHANGE, IS REALLY KEY. IF YOU ASK PATIENTS FOR EXAMPLE, ARE YOU HAVING ACTIVITITY WITH DRESSING, YOU MIGHT HAVE SOMEBODY WHO REPORTS MINIMAL OR NO DIFFICULTY. IT ISN'T UNTIL YOU WATCH THEM PUT A FEW ITEMS ON THAT YOU FIND OUT THAT IS ENTIRELY NOT THE CASE. WE DID THAT STUDY AND PATIENTS ACROSS THE BOARD UNDERRATE THEIR DISABILITY. SO MEASUREMENTS OF PERFORMANCE IS VERY IMPORTANT. >> REALLY IMPORTANT. I THINK THE POINT AT THE BEGINNING, PATIENT REPORTED OUTCOMES WOULD BE PART OF PORTFOLIO TRIAL OUTCOMES INCLUDING BIOMARKERS PROBABLY PLUS PERFORMANCE OUTCOMES AND THEY TELL A MORE COMPLETE STORY WHETHER A DRUG IS WORKING OR NOT, THAN ANY INDIVIDUAL PIECES BY THEMSELVES. KAREN, I WANT TO SWITCH GEARS AND TALK ABOUT SECOND HALF DISCUSSION RECOMMENDATION NUMBER 1 11 MINORITY PARTICIPATION RESEARCH, THESE INITIATIVES INCLUDE RESEARCH TO FACILITATE MINORITY RECRUITMENT AND PD CLINICAL TRIALS. COULD YOU TALK ABOUT ISSUE OF MINORITY RECRUITMENT, THINK MORE BROADLY ABOUT PARTICIPATION OF OTHER GROUPS MAYBE OLDEST OLD OR WOMEN, MEN, WHAT HAVE YOU? >> BIG TOPIC. ONE THING WE HAVEN'T TOUCHED UPON IS THE NEED TO INVOLVE THE ENTIRE COMMUNITY ENROLLMENT OF MINORITIES OR UNDERSERVED GROUP, SO IN THE JUST NEUROLOGISTS -- CAN'T HEAR ME? NOT JUST NEUROLOGISTS, WE NEED TO INVOLVE ALL SORTS OF HEALTH PROFESSIONALS. AND WE ALSO HAVE TO HAVE A HUGE EFFORT ON EDUCATING THE COMMUNITY. IN TERMS OF PROFESSIONAL WE HAVE TO MAKE AN EFFORT TO INVOLVE PROFESSIONALS WHO ARE MINORITY DECENT TO EDUCATE THEM TO GET INTERESTED IN PARKINSON'S DISEASE. THIS INCLUDES RESEARCH ASSISTANCE COORDINATORS IN THE COMMUNITY. AND AS LISA SAID OUT INTO COMMUNITY WHERE IS PATIENTS ARE. WHERE PATIENTS FIND AND EDUCATE THEM. WE CAN TALK ABOUT THIS MORE AS WE TALK ABOUT IN THE GROUP AS WELL SO THAT'S EXTREMELY IMPORTANT, RECOGNIZING THAT SYMPTOMS MAY DIFFER IN DIFFERENT PATIENT GROUPS ETHNIC GROUPS, MAYBE TYPES OF PARKINSON DISEASE IN TERMS OF PHENOTYPE AND GENETIC MARKERS, ALL HAS TO BE PART OF EDUCATIONAL APPROACH TOWARDS THE IMMUNITY. THAT'S NOT JUST MINORITIES, IT'S MEN, WOMEN, EVERYBODY. >> (OFF MIC) >> CAN'T HEAR YOU. ARE THERE ANY SPECIFIC INITIATIVES YOU HAVE BEEN INVOLVED IN THAT ADDRESS THIS? WHAT'S YOUR EXPERIENCE? >> I DON'T HAVE A HUGE EXPERIENCE OTHER THAN MORE IN THE ALZHEIMER'S WORLD WHERE THERE'S MORE A PUSH FOR THIS. ALSO INVOLVED IN ONE OF THE NIMCHT MINORITY RECRUITMENT EFFORTS WITH (INDISCERNIBLE) TO TRY TO UNDERSTAND WHICH ARE SUCCESSFUL AND WHAT STRATEGIES THEY USE FOR MINORITY RECRUITMENT AND BRING IT BACK TO PARKINSON'S DISEASE. >> GREAT. QUESTIONS FROM THE AUDIENCE. >> RICK BURZON WITH THE NIH. THANK YOU FOR TALKING ABOUT HEALTH RELATED QUALITY OF LIFE TOOLS. ONE OF THE FOUNDERS OF A GROUP CALLED THE INTERNATIONAL SOCIETY FOR QUALITY OF LIFE RESEARCH SO IT'S REALLY GRATIFYING AND SATISFYING TO UNDERSTAND NOW THESE KINDS OF TOOLS WE HAVE BEEN WORKING ON FOR YEARS ARE NOW BEING INCLUDED IN THE CLINICAL PRACTICE AND A LOT OF MEMBERS ARE OF COURSE SUPPORTIVE AND WORKED FOR PROMISE. THE RECOMMENDATION YOU MIGHT CONSIDER THESE TOOLS HEALTH RELATED QUALITY OF LIFE OR FDA CALLS PATIENT REPORTED OUTCOMES MEASURES, HAVE BEEN AROUND FOR MANY YEARS AND HAVE NOT BEEN INCORPORATED INTO PRACTICE. AND RESEARCH THE WAY THEY SHOULD HAVE. ONE REASON P FOR THAT IS THAT IT'S NOT IN MEDICAL SCHOOL. IF WE DID A BETTER JOB OF EDUCATING PHYSICIANS ABOUT THESE KINDS OF TOOLS THAT ARE AVAILABLE TO THEM, PARTICULARLY WHEN THERE'S NO CURE FOR PARTICULAR CHRONIC ILLNESS, THE ONLY THING WE CAN DO FOR PATIENTS IS IMPROVE QUALITY OF LIFE, THESE TOOLS MIGHT HAVE BETTER UPTAKE. ONE RECOMMENDATION THAT MIGHT BE POSSIBLE TO MAKE WOULD BE DO JUST THAT, RECOMMEND THIS KIND OF INFORMATION BE TAUGHT IN MEDICAL SCHOOL. I KNOW THE RECOMMENDATIONS ARE GOING PRIMARILY TO CONGRESS BUT THERE MIGHT BE A WAY FOR YOUR COMMITTEE TO INCREASE UPTAKE OF THESE TOOLS. AS THE POPULATION AGES, HE IS TOOLS WILL BE INCREASINGLY IMPORTANT IN CLINICAL PRACTICE AND TREATMENT OF PATIENTS. AND THAT IS WHAT THIS IS ABOUT. THANKS. >> THANK YOU. >> BARBARA TILLEY, I'M THE PERSON THAT CONDUCTED THAT MINORITY RECRUITMENT TRIAL IN PARKINSON'S. I JUST WANTED TO MAKE A COUPLE OF CLARIFICATIONS. PARKINSON'S IS DIFFERENT FROM HYPERTENSION AND MORE COMMON DISEASES, AND IT'S DIFFERENT FROM EARLY, SORRY LATE WHILE MER'S. THAT'S MORE COMMON THAN EARLY ALZHEIMERS SO IF YOU LOOK AT MINORITY RECRUITMENT IN EARLY ALZHEIMERS YOU SEE IT'S LIKE MINORITY RECRUITMENT IN PARKINSON'S. AND THE PROBLEM, IF YOU GO TO A MILLION CHURCHES, YOU MIGHT FIND ENOUGH PARKINSON'S PATIENT BUS THE CHURCH, BEAUTY SHOP, COMMUNITY ISN'T GOING TO HELP YOU THAT MUCH BECAUSE SEARCH AND SEIZURE NOT THAT COMMON A DISEASE. SO WHAT WE FOUND IN THAT TRIAL IS THE HIGHER ENROLLERS, THEIR SUCCESS WITH THE IMMUNITY WAS BASED ON HEALTH FARES. AND WE SPECULATED BECAUSE THEY WERE BUILDING BRIDGES WITH COMMUNITY PHYSICIANS BY HELPING THEM AND HEALTH FAIRS AS SPECIALIST, THERE'S A CERTAIN AM OF LITERATURE THAT SUGGESTS THAT A PATIENT IS MORE LIKELY TO ENROLL IN A TRIAL IF THEIR OWN PHYSICIAN SUGGESTS IT'S A POSSIBILITY. IT'S A GOOD THING TO DO. ALSO THERE'S LITERATURE TO SUGGEST TEACHING PHYSICIANS, THERE WAS A LARGE EFFORT AT THE MINORITY NATIONAL MEDICAL ASSOCIATION, TRYING TO EDUCATE PHYSICIANS ABOUT CLINICAL TRIALS THOUGH EVERYBODY LOVED EDUCATION, IT DIDN'T CHANGE THE PHYSICIANS ENROLLMENT OF PATIENTS IN CLINICAL TRIALS AT ALL. SO I THINK THAT THE SECRET IS TWOFOLD. ONE IS TRYING TO INVOLVE MORE INTERACTION BETWEEN SPECIALISTS AND COMMUNITY PHYSICIANS WHO MIGHT BE SEEING PARKINSON'S. AND I'M NOT SAYING THERE SHOULDN'T BE P MORE PATIENT EDUCATION TO UNDERSTAND WHAT PARKINSON'S IS, BECAUSE PROBLEM A LOT OF PEOPLE SEEKING TREATMENT. WHAT I KEPT HEARING PEOPLE SAY OVER AN OVER PEOPLE MEANING THE SPECIALIST, IT IS NOT WORTH IT. NIH PAYS THE SAME NO MATTER HOW MANY MINORITIES WE ENROLL. THE TIME TO ENROLL MINORITY PATIENTS IS VERY COSTLY, IT'S COSTLY IN TERMS OF FINDING THEM, COSTLY IN TERMS OF RETAINING THEM. SO I THINK ONE OF THE THINGS THAT NIH NEEDS TO RECOGNIZE IS THERE HAS TO BE MORE COORDINATOR AND PERHAPS CLINICIAN SUPPORT IF YOU WANT TO INCREASE MINORITY RECRUITMENT, YOU CAN'T PUT A BOUNTY ON MINORITY PATIENTS, THAT'S UNETHICAL BUT YOU CAN RECOGNIZE ADDITIONAL RESOURCES, MAKE SURE EVERY TRIAL PAYS FOR TRANSPORTATION, FOR PEOPLE WHO NEED IT, MAKING SURE THAT SITE YOU CHOOSE ARE WILLING TO HAVE AFTER-HOURS VISITS. BECAUSE PEOPLE CAN'T NECESSARILY AFOR TO LEAVE THEIR JOBS. ALSO ACCOUNTABILITY AT THE REVIEW STAGE. WHEN YOU'RE ON A STUDY SECTION, MINORITY RECRUITMENT COMES AS AN AFTER-THOUGHT, AFTER THE SCIENTIFIC REVIEW, AFTER THE GRANTS BEEN SCORED, THEN AT THE BOTTOM IT SAYS DO YOU HAVE ANY MINORITY RECRUITMENT CONCERNS. YES, WE'LL ADDRESS THOSE LATER. YET THE PLANS YOU SEE ARE JUST SUPERFICIAL. WE WON'T BORROW ANY MINORITIES AND MAKE GREAT EFFORT TO ENROLL MINORITIES. THERE'S NOT ACCOUNTABILITY. AND EVEN CONGRESS -- THIS IS MY LAST THEN OFF THE PODIUM HERE. EVEN CONGRESS WHO IS TRYING TO MAKE THE INSTITUTES MORE ACCOUNTABLE ALLOWS THEM TO LUMP IN TRIALS THAT ARE 100% MINORITY WHEN COUNTING THEIR STATISTICS. SO IF YOU HAVE AN ALZHEIMER'S TRIAL THAT'S ONLY MINORITY PATIENTS AND YOU ADD IT TO THE DISMAL RECRUITMENT OF EARLY ALZHEIMER'S PATIENTS YOU'LL FIND A VERY DIFFERENT NUMBER THAN JUST TRYING THAT RECRUIT A DIVERSE POPULATION. ACCOUNTABILITY, FINANCIAL SUPPORT, AND A RECOGNITION YOU HAVE TO LOOK IN A DIFFERENT PLACE. >> THANK YOU, DR. TILLEY. GREAT POINTS. WE HAVE TIME FOR A BRIEF QUESTION. >> MY NAME IS (INDISCERNIBLE) UNIVERSITY OF WISCONSIN. I WANT TO GO BACK TO RECOMMENDATION NUMBER 9. THINKING ABOUT THE TRANSLATION AND VALUE OUTCOME MEASURES THAT VALIDATE ANIMAL MODEL WITH SEE IN THE PATIENT. I WANT TO MENTION TWO THINGS. ONE, IF WE USE IMAGING, WE BASICALLY HAVE THE SAME DATA IN ANIMALS AND IN HUMANS, BUT I ALSO THINK THAT NOVEL OPPORTUNITY TO (INAUDIBLE) CAN BE VERY WELL USED IN NON-HUMAN PRIMATES AND HUMANS. ABOUT THE RECOMMENDATION FOR THE NIH TO SUPPORT THAT RESEARCH CREATING TOOLS TO TRANSPLATELET FROM ANIMAL TO HUMAN, A POWERFUL TOOL. >> I THINK WE SUPPORT THAT IDEA ALSO. THANK YOU, AGAIN. WE'RE GOING TO SWITCH TO OUR LAST TALK. CARLY TANNER FROM SAN FRANCISCO WILL TALK ABOUT OPPORTUNITIES FOR UNDERSTANDING AND ADDRESSING DISEASE PROGREG. >> HOW DO WE MAKE IT GO? -- PROGRESSION. >> HOW DO WE MAKE IT GO? OKAY. THANKS VERY MUCH, EVERYONE, FOR GREAT QUESTIONS AND DISCUSSION AND TO HUNDRED DOLLARS NINDS FOR SUPPORTING THIS MEETING. I WANT TO ACKNOWLEDGE THE OTHER MEMBERS OF OUR WORKING GROUP RANDY BATEMAN, (INDISCERNIBLE) AND MATT STERN WHO CONTRIBUTED TO THESE IDEAS. OUR QUESTION AT THE MOMENT IS WHAT DO WE KNOW ABOUT DISEASE PROGRESSION AND HOW WE ADDRESS IT? THIS IS A VARIATION ON THE SCHEMATIC YOU HAVE SEEN A COUPLE OF TIMES ALREADY. AND IN THIS PICTURE, I EMPHASIZE THE VERY LONG PERIOD OF TIME PRIOR TO THE ACTUAL DIAGNOSIS OF PARKINSON'S DISEASE BASED ON MYSTIFIES STATIONS OF MOTOR FEATURES. THERE'S THE PRODROMAL PERIOD WHICH INCLUDES VARIABLE NOT THAT WELL UNDERSTOOD AT THIS POINT ARRAY OF OTHER SIGN AND SYMPTOMSEN COLLUDING IMPAIRED PERCEPTION, OTHER AUTONOMIC CHANGES, CONSTIPATION, RAPID EYE MOVEMENT, SLEEP BEHAVIORAL DISORDER, COLOR CONTRAST SENSITIVITY, CHANGES IN HEART RATE VARIABILITY, MANY OTHER FEATURES THAT CAN BE PRESENT AS WE MENTIONED FOR QUITE A LONG TIME. PRIOR TO ONSET OF MOTOR SYMPTOMS OF PARKINSON'S DISEASE. PRESUMED PERIOD PRIOR TO THOSE CLINICAL MANIFESTATION US TERM PRE-CLINICAL, HEARSAY THE AREA THAT WOULD RELY ON BIOMARKERS THAT SHOW THE BEGINNING OF A DISEASE PROCESS, PRIOR TO THE TIME THAT WE HAVE ANY CLINICAL SYMPTOMS AT ALL. FROM PREVENTIVE PERSPECTIVE YOU WANT TO BE IN THE PRE-CLINICAL PERIOD IDEALLY BUT AT THIS POINT WE'RE NOT ABLE TO IDENTIFY THAT. SO THIS IS OUR DIRECTION. ON AVERAGE HALF THE NEURON LOSS IN THE SUBSTANTIA NIGRA OCCURRED AND THE THREE YEAH TALL DOPAMINE DEFICIT IS 80%. SO HARKING BACK TO DISCUSSIONS EARLIER ABOUT TRIALS AND OUTCOMES OF TRIAL, ONCE WE IDENTIFY SOMEONE WITH PARKINSON'S, IT'S AT THAT MOMENT WE ENROLL IN A TRIAL, THEY HAVE A SIGNIFICANT DEFICIT. THIS SLIDE SHOWS A SCHEMATIC THAT IS BASED ON THE BRAC STAGES OF PATHOLOGY. SO THESE RELATE TO CNS PATHOLOGY, AS WE SAW IN THE PRIOR SLIDE THERE'S ALSO EVIDENCE THERE IS AUTONOMIC PATHOLOGY AND THIS CAN CREED CHANGES IN THE CENTRAL NERVOUS SYSTEM. SO NEURODEGENERATION BEGINS WILL THE BEFORE ONSET OF MOTOR SIGNS AND MAY BEGIN NOT WITHIN THE CENTRAL NERVOUS SYSTEM BUT AUTONOMIC NERVOUS SYSTEM STRUCTURES AND EXTRA CNS TISSUE. IF THIS IS THE CASE WE WANT TO IDENTIFY PEOPLE WILL THE THESE MANIFESTATIONS AND THEORETICALLY THIS IS THE GROUP AT RISK FOR PARKINSON'S DISEASE WHERE WE INTERVENE IN ANY NEUROPROTECTIVE OR DISEASE MODIFYING TRIAL. SO WHAT IS THAT RISK POPULATION FOR PARKINSON'S DISEASE? A NUMBER IS PROPOSED AND SOME ARE ONGOINGING GROUPS OF INDIVIDUALS SO ONE GROUP IS PEOPLE WHO HAVE CLINICAL FEATURES THAT ARE HIGH HI PREDICTSIVE OF THE ONSET OF PARKINSON'S DISEASE IN THE FUTURE. SO THESE HAVE BEEN EVOLVED FROM POPULATION STUDIES WHERE FEATURES ARE MEASURED FOLLOWED PROSPECT TVLY AND SOME DEVELOP PARKINSON'S DISEASE. THIS IS THE GROUP CALLED PRODROMAL PARKINSON'SISM ONE WELL RECOGNIZED IS RAPID EYE MOVEMENT SLEEP MAY HAVE I DON'T RECALL DISORDER, A LARGE NUMBER OF PEOPLE WITH THAT DISORDER OVER 15, 20 YEARS DEVELOP A ALPHA SYNUCLEINOPATHY, PARKINSON'S DISEASE DEMENTIA WITH LOU WII BODY. HYPOSMIA WAS RECOGNIZED IN EARLY FEATURE IN PARKINSON'S DISEASE. PERSONS WITH GENETIC SUSCEPTIBILITY, EASIER GROUP TO CONCEPTUALIZE MOST CLASSIC ARE PEOPLE WITH DOMINANT GENE SO CLASSICAL DOMINANT MUTATIONS IN ALPHA SYNUCLEIN, THE DOMINANT MUTATION ARE PEOPLE WITH TWO COPIES OF THE RECESSIVE GENE SO PEOPLE WITH MENDELIAN DISEASE MOST LIKELY TO GO ON TO DEVELOP P&A DISEASE, THERE'S CAVEATS THERE, NOT EVEN WITH 2 MUTATION GOES ON TO MANIFEST DISEASE. THEN THERE ARE RISK GENOTYPES, PEOPLE WHO HAVE A VARIANT IN A GENE SO THEY'RE AT GREATER RISK OF GETTING THESE BUT IT'S NOT MENDELIAN PATTERN OF INHERITANCE SO ANOTHER SET OF POPULATIONS CHARACTERIZED AND STUDIED TO UNDERSTAND AT RISK AND PROGRESSION. SOMETHING WE HAVEN'T TALKED ABOUT TODAY BUT THAT I THINK IS EQUALLY IMPORTANT, POPULATIONS THAT HAVE EXPOSURE TO TOXICANTS, TRAUMATIC BRAIN INJURY, OTHER EXPOSURES, SOLVENTS THAT ARE RECOGNIZED TO INCREASE RISK FOR PARKINSON'S SO LIKE PEOPLE WITH AT RISK GENOTYPE AND WORK THAT OUR GROUP AND OTHERS HAVE DONE, ALSO SHOWING STRONG GENE ENVIRONMENT INTERACTION SO PEOPLE WHOLE HAVE EXPOSURE PARTICULAR GENOTYPE ARE INCREASED RISK COMPARED TO PEOPLE WITH JUST EXPOSURE OR GENOTYPE. SO THESE ARE THEORETICAL POPULATIONS AT RISK FOR PARKINSON'S DISEASE THAT COULD BE ASSEMBLED AND STUDIES FOR BIOMARKERS OR ENROLLMENT IN CLINICAL TRIALS. THE PREDICTIVE VALUE IS VERY LOW FOR MOST OF THESE AT RISK FEATURES. SO TRYING TO IDENTIFY PEOPLE WITH IMPAIRED SMELL SENSITIVITY IS TIME CONSUMING. MANY DO NOT GO ON TO GET PARKINSON'S DISEASE BECAUSE THERE ARE MANY OTHER REASONS FOR THAT. AND PARKINSON'S DISEASE ITSELF IS RELATIVELY UNCOMMON. YOU SPEND TIME TRYING TO IDENTIFY PEOPLE WITH LOW RISK FOR GOING ON TO THE DISEASE OF INTEREST. SO THIS BECOMES PRACTICAL WHEN DESIGNING POPULATION COHORTS OR CLINICAL TRIALS. WHAT WOULD BE THE IDEAL APPROACH FOR PREVENTING PARKINSON'S DISEASE? OBVIOUSLY WOULD BE IDENTIFY PEOPLE AT RISK FOR DISEASE, HERE THE POINT I MADE YOU NEED AN EFFICIENT SCREENING PROCESS, THIS IS A DILEMMA AT THIS POINT. WE DON'T HAVE AN EFFICIENT SCREENING PROCESS FOR PRODROMAL DISEASE OR PRE-CLINICAL STAGE. NEXT YOU WANT TO INTERVENE TO PREVENT DEVELOPMENT OF MOTOR FEATURES AND HERE YOU NEED SAFE TREATMENT SO IF YOU DEAL WITH PEOPLE THAT DON'T HAVE A DISEASE, DIAGNOSIS PARKINSON'S. SO YOU LOOK AT SOMEONE WITH IMPAIRED OLFACTION AND CONSTIPATION TWO RISK FACTORS FOR DISEASE, YOU DON'T WANT TO GIVE A MEDICINE -- SO SAFETY BECOMES IMPERATIVE AS WELL SO THESE ARE COMPLICATED FEATURES TO CONSIDER VERY EARLY NEUROPREVENTIVE TRIALS. SO WE TALKED ALREADY TODAY ABOUT TRIALS OR DISEASE MODIFYING THERAPIES AND HOW MOST HAVE BEEN INCONCLUSIVE IF NOT CARING TO FAIL. AND THIS RAISES THE QUESTION, WHETHER THAT THE INTERVENTION DIDN'T WORK, THAT WOULD BE AN OKAY ANSWER WE FOUND IT DIDN'T WORK BUT PERHAPS WE JUST INTERVENED TOO LATE. WHAT IF WE HAD INTERVENED AT THAT PRODROMAL PHASE PRIOR TO MAINSTAYS STATION OF THE MOTOR -- MANIFESTATION PRIOR TO 50% LOSS OF NEURONS WOULD WE HAVE BEEN MORE ABLE TO SLOW DISEASE PROGRESSION WITHOUT QUITE SUCH A HIGH BAR TO OVERCOME, AND BE ABLE TO ACTUALLY HAVE A BENEFICIAL EFFECTMENT SO THIS LEADS TO THE QUESTION, CAN IT BE SLOWED OR STOPPED CAN CLINICAL FEATURES BE PREVENTED AND CAN PRODROMAL PD BE PREVENTED IN CAN YOU IDENTIFY BEFORE THOSE MANIFEST. THESE ARE GAPS TO ADDRESS TO TRY TO UNDERSTAND ANSWERS TO THOSE QUESTIONS. THERE ARE MANY UNFORTUNATELY. FIRST WE DON'T HAVE A GOOD DIAGNOSTIC TEST FOR PARKINSON'S DISEASE. IN THE PRESENCE OF CLINICAL PARKINSON'SISM, IF YOU HAVE A SPECIFIC GENETIC MUTATION, YEAH, YOU HAVE A GOOD TEST BUT APART FROM THAT WE DON'T HAVE A DIAGNOSTIC TEST FOR THE DISEASE. WE ALSO DON'T HAVE A GOOD PREDICTOR OF RISK APART FROM THE GENETIC FORM. WE DON'T HAVE A RELIABLE MARKER OF DISEASE PROGRESSION THOUGH WORK IS ONGOING TO TRY TO CHARACTERIZE THIS. WE DON'T HAVE A PREDICTOR OF PROGNOSIS. THESE CLINICAL QUESTIONS ARE CRITICAL TO BEING ABLE TO DESIGN STUDIES THAT WOULD ADDRESS DISEASE PROGRESSION. OTHER AREAS ARE WE DON'T HAVE TREATMENTS TO OUR KNOWLEDGE TO DATE TO PREVENT DISEASE OR SLOW DISEASE PROGRESSION. SO A NUMBER OF CANDIDATES HAVE COME TO THE FLOOR. SOME HAVE SUGGESTED BUT NOT DEFINITIVE EVIDENCE OF DISEASE MODIFICATION. OTHERS NOT AT ALL. SO WE NEED BETTER TREATMENTS TO MOVE FORWARD AS WELL. A CRITICAL MISSING LINK, THIS IS TOUCHED ON AGAIN AND AGAIN AS WELL, IS THE NEED FOR BIOMARKERS. THIS IS A CONCEPTUAL SCHEMA FOR BIOMARKERS OF DISEASE STARTING WITH HEALTHY PEOPLE, MOVING INTO THE DISEASE STATE P PER SE AND THEN YOU COMES OF DISEASE SO THE LATER SEQUELLA OF DISEASE ONCE DIAGNOSED. UNDER THAT I IDENTIFIED THE MARKERS FOR HEALTHY PEOPLE, MARKERS OF RISK, SO THAT'S ARE PEOPLE WITH CLINICAL FEATURE WHOSE MAY HAVE A GENE. WE'RE STARTING TO HAVE A SUGGESTION THAT PERHAPS THERE MAYBE SOME CSF MARKERS THOUGH NOT YET APPLIED TO HEALTHY PEOPLE SO IT'S KIND OF A QUESTION. THERE'S A SUGGESTION THAT YOU MAYBE ABLE TO SEE FOR EXAMPLE ALPHA SYNUCLEIN AGGREGATION IN TISSUES OUTSIDE THE CNS, THIS IS ALL NEW. SOME STILL UNDER EXPLORATION. IN THE GI TRACT PEOPLE ARE INTERESTED IN LOOKING AT OTHER AREAS OF AUTONOMIC FUNCTION TO SEE BIOMARKERS IN TISSUES. IMAGING BIOMARKERS ARE UNDER DEVELOPMENT SO MARKERS OF DOPAMINE FUNCTION OR ALPHA SYNUCLEIN. THEN EXPOSURE GROUPS. GROUPS FOR EXAMPLE, MILITARY DEPLOY PEOPLE WHO HAVE HAD TRAUMATIC BRAIN INJURY ARE CONCEIVED HEALTHY, IF THEY'RE NOW RECOVERED OR AT RISK OR WORKERS EXPOSED TO A CERTAIN CHEMICAL T. PRODROMAL PHASE WE DISCUSSED, WE HAVE CLINICAL SIGNS OR SYMPTOMS, THEN THE OTHER BIOMARKERS, IMAGING CSF OR TISSUES ARE IMPORTANT. ONCE DIAGNOSIS IS MADE, THERE'S QUESTION OF WHAT THE PROGNOSTIC SIGNIFICANCE IS. CAN WE FIND BIOMARKERS THAT ADDRESS DISEASE PROGRESSION, THIS PERSON RAPIDLY OR SLOWLY PROGRESS. WE HAVE A LITTLE BIT OF CLINICAL EVIDENCE, TREMOR DOMINANT VERSUS POSE DO YOU RECALL STABILITY, GATE DISORDER, ARE THERE OTHER BIOMARKERS THAT CORRELATE WITH THAT, PRELIMINARY SUGGESTIONS, MAYBE BUT MORE WORK NEEDS TO BE DONE. THEN FINALLY MARKERS OF DISEASE PROGRESSION, PRELIMINARY WORK SUGGESTING THAT CSF RATIO, ALPHA SYNUCLEIN TAU OR OTHER MEASURES MAY GIVE US A DISEASE PROGRESSION MEASURE. BUT SO FAR WE HAVE NO WAY TO SHOW DISEASE IS PROGRESSING. THAT'S THE CRITICAL CONFOUND ONCE REQUIRING SYMPTOMATIC THERAPY. SO HOW WILL WE FIND OUT? FIRST STUDY EXISTING POPULATIONS ABOUT RESOURCES, EXAMPLES OF THESE, THESE ARE JUST SOME, PERSPECTIVE COHORTS WITH CLINICAL BIOLOGIC DATA, HONOLULU AGING STUDY AUTOPSY AND RISK FACTORS, ARIZONA PARKINSON'S DISEASE CONSORTIUM, AUTOPSY, THESE ARE CHARACTERIZED POPULATIONS, PAR STUDY, PARKINSON'S PROGRESSIVE MARKER INITIATIVE. AND GENETIC COHORTS ESTABLISHED AND WILL BE FOLLOWED PERSPECTIVELY. THESE POPULATIONS NOW BEING STUDIED BUT COME BACK TO THE POINT LAST SESSION, FOLLOWING PERSPECTIVELY THROUGHOUT THE COURSE OF DISEASE BECOMES MORE DIFFICULT AND EXPENSIVE. CLINICAL TRIAL POPULATIONS LIKE THE DATA -- ARE A STARTING POINT BECAUSE THEY'RE WELL CHARACTERIZED AND CAN BE FOLLOWED EFFICIENTLY TO THE END OF DISEASE. THEN THERE ARE THE BIG DATA POPULATIONS KEISER PERMANENTE, CMS, WHERE YOU MAY GET CERTAIN KINDS OF INFORMATION AND NOT OTHERS PERSPECTIVELY BIOSPECIMEN REPOSITORY, THESE WERE DISCUSSEDDED EARLIER BY DR. LANDIS, THESE ARE IMPORTANT RESOURCES. LASTLY WE NEED TO INITIATE NEW STUDIES ESTABLISH DATA TISSUE REPOSITORIES, DETERMINE RISK PROGNOSTIC MARKERS, CLINICAL BOY LOGICAL DEVELOP EFFICIENT SCREENING FOR AT RISK POPULATION S. PROOF OF CONCEPT PREVENTION TRIALS IN HIGH RISK POPULATIONS, THIS WILL NOT BE ACHIEVED WITHOUT COLLABORATING WITH BASIC SCIENCES FOR DISCOVERY AND VALIDATION OF BIOMARKERS, AND ALSO FOR IDENTIFYING DISEASE MECHANISMS AND THERAPEUTIC TARGETS. THIS HAS TO BE AN ITERATIVE COLLABORATIVE PROCESS TO BE ABLE TO BE SUCCESSFUL. SO I WILL END WITH RECOMMENDATIONS FROM OUR GROUP WHICH WERE AMONG THE MOST LIELY RATED OF OUR SECTION. OF GREAT INTEREST. WANT TO CONVENE THE PANEL NOW. YES. >> SO THIS IS OUR LAST PANEL DISCUSSION. WE HAVE 20 MINUTES TO DISCUSS CURRENT TOPIC DISEASE PROGRESSION. THEN 30 MINUTES OF OPEN DISCUSSION WE CAN GO BACK AN DISCUSS ANY TOPICS OR THEMES THAT EMERGED FROM THE MORNING. BEFORE WE START I WANT TO THANK THE PANELISTS TODAY WHO BASICALLY DID TWICE AS MUCH PANELING AS THEY HAD COME HERE EXPECTING TO DO AND THEY HAVE DONE A YEO MAP'S JOB. I CAN'T THANK DR. TANNER AND DR. POEWE ENOUGH FOR BEING ACTIVE PARTICIPANTS AND THOUGHTFULNESS AND DEDICATION DURING THE MORNING. (OFF MIC) >> THEY'LL BE RECRUITING. THEY HAVE AN RBD COMPONENT, RECRUITING AND ALSO A FACTRY DEFICIT, CONFERENCE CALL I WAS ON JUST A SHORT WHILE AGO SAID PATIENTS ARE STARTING SUBJECTS ARE STARTING TO COMMIT SO THAT'S GOOD NEWS. I WOULDN'T FORGET ADNE A DEATH SET TO GO TO LOUIS BODY DISEASE BECAUSE 22 SUBJECTS WOODIED IN ADNE HAD AUTOPSY WITH MILD COGNITIVE IMPAIRMENT OF MCI TYPE OR ALZHEIMER'S TYPE. ONLY FOUR OF THE 22 HAD PLAQUE AND TANGLE ONLY. PATHOLOGY. THIRD LOUIS BODIES WITH AD PATHOLOGY, WE'RE MEASURING ALPHA SYNUCLEIN IN THAT COHORT. WITH ALZHEIMER'S DISEASE MAY HAVE ADDITIONAL LOU WII BODY DISEASE SO ADDITIONAL COHORT TO KEEP THIS MIND. >> THIS IS REALLY INTERESTING. I HOPE WE'LL HAVE A CHANCE TO RETURN TO THOSE THEMES OPEN SESSION THE LAST HALF HOUR. AS YOU CAN SEE WE HAVE THREE TOP RATED RECOMMENDATIONS, TWO WHICH HAD TO DO PRODROMAL PARKINSON DISEASE ONE PROOF OF CONCEPT PREVENTION TRIALS AND TWO CONDUCT STUDIES TO DEFINE NATURAL HISTORY OF PRODROMAL PD. PREDICATED ON THE IDEA EARLY TREATMENT IS BETTER AND MORE EFFECTIVE. CAN YOU GIVE PROS AND CONS AND EXPLAIN WHY YOU FELT THIS WAY? >> HOPEFULLY APPROPRIATE. >> I THINK WHEN WE WERE IN THE HEYDAYS OF DISEASE MODIFICATION OR NEUROPROTECTION TRIALS, WE MAYBE TOO LATE AS A REASON OF FAILURE. IN THAT SENSE NOT SURE IF EARLY RISK IS BETTER. THE CHILD MAY NOT BE EASIER. IF YOU TALK DISEASE MODIFICATION, ESTABLISH DISEASE BECAUSE YOUR SIGNAL MAYBE LOW, YOUR SENSITIVITY MAYBE LOWER FOR AN AGENT. YOU MAY NOT GET OUT OF DILEMMA BUT IF YOU TARGET AS I THINK ONE SHOULD, THE IDEA OF PREVENTING DISEASE AND PREVENTION MEANING DELAYING ONSET, THEYING ONSET, IT'S CRITICAL TO BE EARLY AND TO DEFINE AS POINTED OUT WITH HELP OF MARKERS WHATEVER MEANS WE MIGHT HAVE AT RISK POPULATION AND STUDY INTERVENTIONS BY VIRTUE OF THEIRANT TO DELAY CON VERSIONS. SO FROM THE PERSPECTIVE OF THE HEALTH PERSPECTIVE POPULATION PERSPECTIVE COMING TO THE GOAL OF PREVENTING OR DELAYING ONSET IS REALLY CRITICAL. >> THANKS. FOLLOWING UP ON RECOMMENDATIONS 1 AND P 2, I WANT TO ASK YOU CAR LEE, YOU ALLUDED TO THE IDEA PARKINSON'S IS NOT VERY COMMON IN PRODROMAL -- I KNOW YOU TALKED EARLIER. THE IDEAL WAY IT WOULD BE EFFICIENTLY DONE IS BIOMARKER PREDICTED THAT SOMEONE WAS LIKELY TO DEVELOP DISEASE AND CHANG THAT NCI THAT BIOMARKER THAT CHANGES OVER TIME SO THAT YOU CAN MONITOR. THAT WOULD BE THE IDEA, WE DON'T HAVE -- AT THIS POINT WE'RE EXPLORING SHALL I SAY, USING A STAGED APPROACH THAT STARTS WITH SOME RISK FACTORS SO COMBINATION OF GENETIC AND OLFACTORY DEFICIT AND THEN COMBINING THAT WITH IMAGING MARKER, NEXT STAGE MARKER, WHERE YOU CAN SEE BORDERLINE CHANGE THIS IS THE KIND OF DESIGN WE'RE WORKING WITH IN PPMI AS JOHN MENTIONED. FOLLOWING PEOPLE PERSPECTIVELY. WHICH OF THOSE WOULD BE MOST PREDICTIVE OF PARKINSON DISEASE, AT THIS POINT I DON'T KNOW APART FROM BEHAVIOR DISORDER THE ANSWER TO THAT, PERHAPS MAJOR MUTATIONS, THINGS LIKE THAT. SO THERE'S WORK TO BE DONE. THERE'S ANOTHER APPROACH PLAYING WITH, COMPLETELY DIFFERENT BIG DATA APPROACH, LOOKING AT PEOPLE WHO HAVE DIAGNOSES, OF THOSE PRODROMAL FEATURES AND LOOKING AT WHETHER THAT MIGHT BE A PASSIVE WAY TO IDENTIFY PEOPLE BUZZ THEY COME INTO THE HEALTHCARE SYSTEM COMPLAINING OF PONS CONSTIPATION. YOU MAY DO A SECOND OLFACTORY MEASURE. IF THAT WAS ABNORMAL YOU FURTHER THING MAJIG. >> THANKS. CAROL, YOU HAVE BEEN INVOLVED IN THE RESEARCH AND OTHER GENETIC RESEARCH WITHIN CORE PD. COULD YOU TALK ABOUT HOW GENETICS CAN BE HARNESSED TO IDENTIFY PRODROMAL COHORTS? WHAT THE PROS AND CONS ARE? >> ONE THING WE HAVEN'T TALKED ABOUT IS PENETRANTS. THERE'S A WIDE VARIETY OF PENETRANTS, WHICH IS DOMINANT DEPENDING THE STUDY, ANYWHERE FROM 20 TO 80%. WE ASKED ABOUT GENETIC KNOWLEDGE ASH CANOESIVE JEWISH CONSORTIUM AND IT WAS INTERESTING. DO YOU WANT GENETIC TESTING TO IDENTIFY PEOPLE, EVERYONE SAYS YES. BUT IF YOU GET A NUANCED APPROACH, YOU HAVE A 90% CHANCE, 50%, 20% CHANCE OF DEVELOPING PD OVER LIFETIME, DO YOU WANT TESTING? AND CORRELATED BEAUTIFULLY. IF YOU HAVE A 90% CHANCE EVERYBODY WANTS IT, IF IF YOU HAVE 25% ONLY 25% WANTS TESTING INITIALEST ANYTIME OF PENETRANTS IN THE IMMUNITY IS 25%. SO THAT'S EQUIPOISE SO WE NEED TO EDUCATE INDIVIDUALS AND FAMILIES BECAUSE IF YOU HAVE TO TELL SOMEBODY THEY CARRY A MUTATION AND THERE'S 25% RISK TO DEVELOP IT OVER THEIR LIFETIME THEY MAY OR MAY NOT WANT TO BE TESTED. AND WE HAVE TO THINK HOW THAT MAYS OUT IN TERMS OF OBSERVATIONAL STUDIES AND CLINICAL TRIALS HOW TO E DIDN'T TRIALS THAT PROTECT PEOPLE'S WISH NOT TO KNOW. NOT NECESSARILY TO KNOW. AS WE THINK ABOUT INVOLVING FAMILY MEMBERS IN GENERAL, IF THEY DON'T PERCEIVE AT RISKER O NOT NECESSARILY LIKELY TO WANT TO PARTICIPATE IN TRIALS, SOME OF WHAT WE TALK ABOUT EARLIER IN TERMS OF REMOTE ACCESS TO PATIENTS HAS TO BE COMBINED. THE TENSION IS THAT THE BIOMARKERS THAT MAYBE MOST INFORMATIVE ARE THOSE CSF. THOSE REQUIRE PEOPLE TO COME IN AND COMMIT TO TIME AND EFFORT AS FAMILY MEN WHO MAY OR MAY NOT PERCEIVE THEY'RE AT RISK. THESE ARE THINGS TO CONSIDER CAREFULLY AS WE DESIGN OUR STUDIES, AS WE IDE FEW PEOPLE AT RISK ON A GENETIC BASIS. >> A FOLLOW UP QUESTION FOR YOU OR OTHER MEMBERS OF THE PANEL. IF WE DID A TRIAL IN HOW DO YOU INTERPRET THE RESULTS OF THAT STUDY IN CONTEXT OF NON-GENETIC PARKINSON'S? WHAT IS THE CARRY OVER BETWEEN THESE HOMOGENOUS GENETICALLY DEFINED POPULATIONS IN PD MORE BROADLY DEFINED? >> I DON'T KNOW THAT WE KNOW THAT. WE NEED TO DO RELATED PARALLEL STUDIES LOOK AT QUOTE SPORADIC AND NO MENDELIAN GENE CARRIERS AND YOU SEE WHAT MARKERS ARE THE SAME OR DIFFERENT. THAT'S THE WAY WE'LL FIND OUT. >> >> TO ADD TO THIS, THIS IS DEBATE PUSHING AHEAD WITH A FIRST PROOF OF CONCEPT PREVENTION TRIAL IN SOME POPULATIONS PEOPLE SAY, LET'S GO FOR SOMETHING THAT IS A VERY HIGH RISK RBD SMALL POPULATIONS BUT WE WOULD GET A RESULT AND THEN IT COMES TO -- IT WOULD BE ENORMOUS WHATEVER WE LEARN FROM IT WE WOULD HAVE IN A POSITIVE TRIAL, FIRST EVER EXAMPLE OF SOME SUBGROUP OF PARKINSON'S DISEASE WHERE A GIVEN PRINCIPLE OF TREATMENT WOULDN'T WORK. THEN IT REQUIRES LOST OF TESTING APPROXIMATE FURTHER TRIALS IN OTHER POPULATIONS BUT IT WOULD BE, I WOULDN'T KNOW HOW TO INTERPRET OTHER THAN TREMENDOUS RAY OF HOPE. >> LET OWE JEFFREYTY IS AN ISSUE WE DONE -- HETEROGENEITY IS AN ISSUE WE DON'T UNDERSTAND WELL BUT EVEN PICKING A HOMOGENOUS GROUP NOT REPRESENTEDDED WOULD GIVE US A TREMENDOUS AMOUNT OF INFORMATION JUST ABOUT HOW TO APPROACH PEOPLE AND ASK THEM ABOUT BEING INVOLVED IN THE STUDY LIKE THIS. >> HI, (INAUDIBLE) LONDON. ONE THING WE HAVE DONE IN RICH POPULATION FOR PARKINSON'S DISEASE IS TO RECRUIT AND U WONDER IF YOU GUYS OVER HERE RECRUIT (INAUDIBLE) PARENTS AND GRANDPARENTS IN A SYSTEMATIC FASHION THROUGH THE SOCIETY. THIS IS BEEN QUITE CLEAR THAT A LOT OF THEM, TONY SHAPIRO LOOKED AT A LOT AND THEY HAVE A LOT HAVE WHAT LOOKS TO BE PRODROMAL DISEASE, EVEN IF NOT ALL GO AND DEVELOP THE FULL DISEASE. THAT'S ONE WAY TO GET QUITE A LARGE POPULATION, QUITE EASILY AND QUITE QUICKLY. >> FOLLOW-UP ON THIS. >> AS PART OF HIS K AWARD KO-2 AWARD HE'S RECRUITED PEOPLE RELATIVES OF GOSHAY PATIENTS AND THE INITIAL PENETRANTS ARE ACTUALLY EXTREMELY LOW, CARRYING A MUTATION THAT'S 10% IN HIS HANDS. >> I AGREE WITH YOU, THAT'S I THINK PROBABLY RIGHT. ACTUALLY IF YOU LOOK AT THE OTHER PRODROMAL SYMPTOMS OF PD, IT'S A LOT HIGHER THAN THAT. OLFACTORY PROBLEMS SUGGESTING THEY HAVE SOME -- I AGREE WITH YOU BUT 10% IS STILL TENFOLD FIVE TO TENFOLD ENRICHMENT, AND THEN IF YOU STARTED TO DO PHENOTYPIC THINGS, YOU'RE INTO BALLPARK MORE EFFICIENT THAN OUT TO GENERAL POPULATION. >> QUESTION, IT'S A GREAT IDEA, BY QUESTION WAS WHAT DOES THE PANEL THINK OF THE PRACTICAL TIME FRAME OF A PREVENTION TRIAL? WOULD IT BE ONE YEAR? IF YOU TAKE A BEST CASE SCENARIO YOU GET A BUNCH OF RBD CASES, CONVERSION COULD BE 10, 20 YEARS. SO IS THERE SOME INTERMEDIATE THAT YOU COULD USE AS YOU COME MEASURE RATHER THAN CONVERSION PER SE? >> I WAS GOING TO ASK WARNER OR LISA TO TACKLE THAT IN TERMS OF OTHER BIOMARKERS TO MEASURE CHANGE PRODROMAL PD. WHAT WOULD THE CLINICAL OUTCOME MEASURE LOOK LIKE? COMMENT ON ONE PART OF THE QUESTION, WOULD FEE KNOW CONVERSION BE REALISTIC? AND WHEN WE PERFORMED OUR POPULATION COHORT STUDY OF PEOPLE AGED ABOVE 15 WHO WE FOLLOWED WITH ULTRASOUND WE DID A MID BRAIN ULTRASOUND AT BASELINE WE WERE INTERESTED IN THIS ULTRASOUND SIGNAL WHICH PEOPLE CLAIM MIGHT BE RISK MARKER, WE FOUND IT WAS. CONVERTED 17 FOLD INCREASE IN RISK TO OVER THREE YEARS DEVELOP PARKINSON'S IN THAT POPULATION OF 1800 PEOPLE AND WE MADE SOME CALCULATIONS SO YOU CAN FEASIBLY IF YOU HAVE THE RIGHT POPULATION START WITH FEE KNOW CONVERSION IN A THREE YEAR STU DI. BASED ON THE RESULTS WE HAD USING AGE ABOVE 50 PLUS ULTRASOUND POSITIVITY. WE WOULD HAVE NEEDED AN INTERVENTION THAT HAS A 30% RISK REDUCTION PROPERTY. SO IT IS FEASIBLE THEORETICAL TERMS, LOTS OF DIFFICULTIES, AWARE OF THAT BUT JUST TO -- FEE KNOW CONVERSION IS NOT OUT OF THE QUESTION AS AN OUTCOME. >> IN THINKING FEE KNOW CONVERSION LOOKING AT T THE SLIDE OF THE MARKERS OF RISK AND THE MARKETS OF PRODROMAL PD, I WAS WONDERING IF THERE'S ANY WORK, I CAN'T RECALL IN TERMS OF LOOKING AT PERFORMANCE. PHYSICAL PERFORMANCE IF YOU UNDERSTAND PARAMETERS OF NORMAL GATE SPEED FOR DIFFERENT AGE GROUPS FOR EXAMPLE, OBVIOUSLY EXCLUDING OTHER CAUSES THAT COULD INTERFERE THAT COULD HELP US BE MORE SENSITIVE IN TERMS OF IDENTIFYING FEE KNOW CONVERSION THAN THERE ARE RIGHT NOW. OUR ACTUAL ABILITY TO SAY FOR THIS PERSON THIS IS VERY SUBJECTIVE, VERY OFTEN NONE CAN DO THE WAY WE WANT TO DO. QUANTITATIVE MEASUREMENT WOULD HELP. >> THERE'S THE BEGINNING OF MEASUREMENT SO AGAIN, I KNOW ABOUT PPMI AND PPMI SOME OF THE MOTOR TASK LIKE REPETITIVE TAPPING REACTION TIME, TIMES OF TASK AND POSSIBLY ALSO SOME MEASURES OF AXIAL STABILITY THAT IN OTHER POPULATIONS, THIS IS AN AREA -- LARK CARRIERS SEEMS TO BE RELATED TO PRODROMAL GREATER RISK OF MANIFEST DISEASE. SO PEOPLE ARE STARTING TO LOOK AT THAT AND THOSE ARE VERY IMPORTANT THINGS TO MEASURE. >> I WANT TO CLEAR -- TAKE SOME TIME BEFORE TIME FOR THIS DISCUSSION PERIOD RUNS OUT TO LOOK AT RECOMMENDATION 3 OBVIOUSLY PRODROMAL IS VERY INTERESTING BUT OTHER VARIATION NUMBER 3 LONGITUDINAL STUDIES BIOMARKER RANDOMIZED CLINICAL TRIALS DATA SPECIMENS SHARING RESOURCES TO CHARACTERIZE COURSE PD. IT'S A LONG RECOMMENDATION. CARLY WOULD YOU UNPACK IT AND TALK ABOUT WHAT KINDS OF APPROACHES YOU ENVISION AS PART OF THIS RECOMMENDATION? >> THIS IS A SORT OF AFTER PRODROMEAL, THE IDEA IS TO HAVE A SIMILAR COMPLIMENT OF BIOMARKER AND CLINICAL OBSERVATIONS TO BE ABLE TO CHARACTERIZE THE NATURAL HISTORY OF PARKINSON'S DISEASE AND HETEROGENEITY. SO WE TALKED EARLIER ONCE YOU START TREATMENT, MANY CLINICAL MARKERS ARE HARDER AS MARKER OF PROGRESSION. SO THIS IS TO DEVELOP ALSO A REPOSITORY THAT COULD BE USED TO BE ABLE TO UPS MORE ABOUT DISEASE PROGRESSION. >> WHILE YOU SPEAK COMMENT ON RECOMMENDATION NUMBER 8 TO DETERMINE FACTORS THAT COULD FACILITATE PUBLIC HEALTH INTERVENTIONS INCLUDING RISK FACTOR REDUCTION INTERVENTIONS THIS DOVE TAILS WITH EARLY DETECTION BUT THERE'S OTHER ASPECTS AS WELL. >> THIS WOULD BE FOR EXAMPLE, WAYS TO TRY TO USE A POPULATION APPROACH TO IDENTIFY PEOPLE WHO MAYBE AT RISK. SOME OF THE RISK FACTORS TO BE AWARE OF FOR GOING TO SEE YOUR DOCTOR FOR POSSIBLE CARDIOVASCULAR RISK, PARKINSON'S NEURODEGENERATIVE DISEASE AND INTERVENTIONS THEORETICALLY PUT THESE AS SIMPLE, BENIGN BUT AS SIMPLE AS REGULAR EXERCISE GOOD FOR PREVENTING PARKINSON'S DISEASE, EVERYONE SHOULD DO REGULAR EXERCISE AND POPULATION TRIALS IF YOU HAVE THE RESOURCES TO TEST EFFICACY OF THAT OR NOT. >> ENCOURAGE SMOKING? >> NO. >> THANK YOU VERY MUCH, JOHN DO YOU HAVE A QUESTION? >> OBSERVATION ON PREVENTION TRIALS IS THREE ARE FUNNED AND GOING FORWARD IN ALZHEIMER'S DISEASE RIGHT NOW, I PARTICIPATE IN SOME BUT NOT ALL THE PLANNING SESSIONS AND THEY WENT ON FOR THREE OR FOUR YEARS BEFORE NOMINATEING A DRUG THAT WOULD BE TESTED FOCUS ON PLANNING, ONE IS THE DIANE STUDY -- >> RANDY IS ON THE PHONE. >> HE CAN COMMENT ON THAT, MORE DETAILS THAN I HAVE, THERE'S THE COLUMBIA FAD CLINICAL TRIAL 5,000 MEMBERS OF THIS VERY LARGE FAMILY HAVE THE MUTATION 500 PEOPLE DO NOT HAVE DISEASE AND I BELIEVE THEY ARE GOING TO COGNITIVE IMPAIRMENT TO DEATH SO THEY HAVE GOOD PREDICTIVE NUMBERS OF WHEN PEOPLE SHOW MCI HOW LONG THEY'LL LIVE OR WHEN THEY WILL DEVELOP MCI SO YOU CAN DESIGN THE TRIAL TO DELAY MCI OR DELAY DEMENTIA. THEN THERE'S THE RHESUS A-4 TRIAL PEOPLE NORMAL COGNITIVELY BUT HAVE TWO ARCPOE 4 ALLELES WHICH INCREASES RISK 15 FOLD. AND THEY'RE BIOMARKER POSITIVE AMYLOID IMAGING POSITIVITY. THEY MAYBE BRINGING TAU IN BUT THERE'S A WEALTH OF INFORMATION WE CAN DRAW UPON, PARKINSON'S IS A DIFFERENT DISEASE OF COURSE. THERE IS A LOT OF DIFFERENCES AT THE BIOMARKER AND GENETIC LEVEL THAT CAN TAKE PLACE BEFORE WE KNOW WHAT DRUG WE'RE GOING TO TRY IF WE WANT TO CONSIDER PLANNING FOR A PREVENTION TRIAL. >> REALLY GOOD COMMENTS. ARE YOU THERE RANDY? >> YES. >> I WAS HOPING THAT THE DIANE STUDY OBVIOUSLY A GREAT MODEL FOR THINKING ABOUT PREVENTION TRIALS, COULD YOU SHARE YOUR EXPERIENCE A LITTLE BIT MAYBE SPECIFICALLY LESSONS LEARNED FROM DIANE USEFUL FOR PLANNING A PARKINSON'S INTERVENTION TRIAL? >> SURE. A FEW KEY THINGS. ONE IS AS I WAS LISTENING TO THIS SESSION MANY OF THESE THINGS WERE SPECIFIC RECOMMENDATION OR CHALLENGES FOR THE PARKINSON'S DISEASE AND SOME HAVE TO DO WITH RECRUITMENT OF IN MANY CASES PEOPLE WITH MUTATIONS ARE KIND OF A MINORITY POPULATION IN THERE ARE EXTREMELY RARE AND GEOGRAPHICALLY DISPERSED. SO SPECIAL EFFORTS NEED TO BE TAKEN IN TERMS OF RECRUITMENT AND MAKING IT POSSIBLE TO PARTICIPATE, TYPICALLY VERY INTERESTED AND ENGAGED. FOUR BASIC INGREDIENTS TO SUCCESS. AND ENGAGE POPULATION DISCUSSION TRIALS EARLY ON IS IMPORTANT AND TIERING COMMITTEE WE HAVE SEVERAL MEMBERS BUT WE HAVE REMEMBER WEBINARS WITH SOMETIMES HUNDREDS OF PEOPLE PARTICIPATING IN THIS SUCH AS OBSERVATIONAL TRIALS. THE SECOND THING, ENGAGING BOTH NIH AND WITH REGULATORS IN THE U.S. AS WELL AS EUROPE AND OTHER AREAS. THINKING ABOUT THESE TRIALS IS A SPECIFIC CHALLENGE. THE REGULATORS HELP IN TERMS OF WHAT'S FEASIBLE, WHAT THE OUTCOME MEASURES WOULD BE, WHAT KINDS OF TRIALS THIRD IS THE ACADEMIC COMMUNITY WHICH TO A LARGE EXTENT HAS BEEN VERY ENGAGED BROADER ACADEMIC COMMUNITY, MANY FOLLOW PATIENTS AND FAMILIES IN A VARIETY OF AREAS ARE CRITICAL (INAUDIBLE). ONE NEEDS TO HAVE OUTSTANDING (INAUDIBLE) (INDISCERNIBLE) >> RANDY YOU BROKE UP A LITTLE BIT. CAN YOU REPEAT THE LAST 20 SECONDS OR SO? FOURTH TOPIC? >> ONE NEEDS TO HAVE EXCELLENT DRUG CANDIDATES AND FOR THE PROCESS WHICH VERY PREVENTION TRIAL VERSUS USED TO EVALUATE DRUG CANDIDATES, ONE THING DIANE HAS DONE IS HAVE A DIANE FORM A CONSORTIUM 12 PHARMA PARTNERS THAT ALL SIT AT THE TABLE AND DISCUSS ISSUES OF THESE TRIALS APPROXIMATE NOMINATE TO BE CONSIDERED TO BE USED IN THESE TRIALS. AND DIANE WHAT WE HAVE DONE IN THE DIANE 2 TRIAL IS STARTED WITH MULTIPLE DRUGS AND MULTIPLE TARGETS. AND TRIED TOCOTHIS IN A WAY TO ALLOW US TO INDICATE EARLY STAGE USING IS SAFE TOLERABLE AND ENGAGE THE BIOMARKER. COVERED EARLIER IN THE SESSION AND POTENTIALLY IN PARKINSON'S. >> GREAT. I THINK THAT'S A GREAT MODEL FOR US. SO WE HAVE ABOUT 20 MINUTES LEFT FOR OPEN DISCUSSION. WE HAVE A FEW QUESTIONS THAT CAME IN VIA THE INTERNET AND WE WILL TAKE THE QUESTIONS FROM THE AUDIENCE AND MOVE TO OTHER PEOPLE WHO HAVE COMMENTS PLEASE DO COME UP. >> MY NAME IS (INAUDIBLE) I'M A PARKINSON'S PATIENT FOR THE PAST 7 YEARS. THE (INAUDIBLE) FACING THE PARKINSON'S PATIENTS AS THEY CAN SEE FROM THE GROUP DISCUSSION THAT I GO SUPPORT SESSION IS HARD TO INCREASE THE QUALITY OF LIFE HOW CAN I GO ON SOCIETY THAT LEADS TO TREMOR AND HOW CAN I DRIVE THE CAR WITHOUT ANY PROBLEM? THAT KIND OF -- MOST IMPORTANT ASPECT, THINGS FOR PATIENTS AND I THINK THE QUALITY OF LIFE CAN BE INCREASED ONLY BY INCREASING QUALITY OF CARE. WHICH IS RELATED TO THE NUMBER OF PHYSICIAN WHOSE ARE TRAINED IN THE PARKINSON'S DISEASE THAT ARE ONLY TWO OR THREE PARKINSON'S IN ALL OF MARYLAND. I WOULD LIKE TO KNOW WHAT RECOMMENDATIONS TO TRAIN NEUROLOGISTS STARTING WITH THIS STATE SO THAT THE PARKINSON'S PATIENTS CAN BE BETTER INFORMED TO BETTER INCREASE THE QUALITY OF LIFE. >> THANK YOU FOR THAT REALLY IMPORTANT QUESTION. SO STARTING WITH THE BEGINNING QUESTION ABOUT QUALITY OF LIFE. ACTUALLY YOU'RE SEEING THE TOP 12 RECOMMENDATIONS OF THESE VARIOUS GROUPS BUT THERE ARE MANY OTHER RECOMMENDATIONS TOO. SOME, AT LEAST ONE THAT COMES TO MIND REALLY FOCUS CAND ON THIS. THAT DEALS WITH THE ISSUE KNOWN AS SELF-EFFICACY FOR MANAGING YOUR CONDITION. THE CONCEPT YOU'RE BRINGING OUT IS LIVING WITH PARKINSON'S DISEASE SYMPTOMS AND KNOWING HOW TO MANAGE IN THE WORLD, MAYBE EXPLAINED TO OTHERS WHAT DIAGNOSIS IS BECAUSE YOU HAVE ABOUT OBVIOUS TREMOR AND MAINTAINING FINDING WAYS TO FIND QUALITY OF LIFE HAVING TO COPE WITH MANAGING MEDICINES TREATMENTS AND SO FORTH, SOMETHING WE COULD BE TRAINED ON. ANOTHER AREA OF RECOMMENDATION THAT DID NOT MAKE IT BUT OBVIOUSLY THESE WERE ALL IMPORTANT RECOMMENDATIONS, IS TO STUDY ACTUALLY TRAINING PEOPLE FROM THE TIME THEY HEAR OF THE DIAGNOSIS ABOUT HOW TO MANAGE IN THE REAL WORLD WITH A DISEASE. THAT POTENTIALLY WOULD BE A WAY TO ENHANCE QUALITY OF LIFE IN TERMS OF THE SECOND PART REGARDING TRAINING MORE PHYSICIANS TO GO INTO PARKINSON'S MOVEMENT DISORDERS SPECIALISTS, I COMPLETELY SUPPORT THAT. I THINK THAT EXTREMELY IMPORTANT BECAUSE WE DO BELIEVE PATIENT WHOSE ARE RECEIVING SUBSPECIALTY CARE FOR MOVEMENT DISORDER SPECIALISTS DO BETTER LONG TERM SO I COULDN'T AGREE MORE. >> THE SUPPORT GROUPS DEVELOPED BY PARKINSON'S FOUNDATION OF NATIONAL (INAUDIBLE) I DO NOT SEE ANY OF THESE IN THAT BIG POPULATION PARKINSON'S PATIENTS. AT LEAST 900 PATIENTS IN THE PARKINSON'S FOUNDATION LIVED AND I WOULD APPRECIATE IF THIS INFORMATION COULD BE DETERMINED, IF YOU CAN ASK THE FOUNDATION THEY WILL BE GIVING YOU THE LIST FOR THE PATIENTS AND WHO CAN BE INFORMED BETTER VIA EMAIL ET CETERA. >> THANK YOU FOR THAT QUESTION. WE'LL PROBABLY RETURN TO THIS THEME OF PATIENT ENGAGEMENT AND RESEARCH AND CARE AGAIN SOME OF THE QUESTIONS THAT CAME IN FROM THE INTERNET. FROM Z I WOULD LIKE TO TAKE ONE MORE QUESTION FROM THE AUDIENCE THEN MOVE TO QUESTIONS THAT CAME IN AND THEN BACK TO THE AUDIENCE. SO GO AHEAD. >> ONE HAD TO DO WITH SORT OF A COST AND POWER BEHIND CLINICAL TRIALS DESIGNIOUS EAR PROPOSING AND ESPECIALLY PREVENTION TRIALS, FOR EXAMPLE WITH M DISEASE IT'S ALSO DOCUMENT ASSOMAL DOMINANT PEOPLE BEGAN TRIAL BUS THERE'S LESS POWER MIND THOSE TRIALS. I WAS CURIOUS WHAT IMPACT THIS WOULD BE ON THE COST. THE SECOND ONE TO RETURN TO A QUESTION, RAISED EARLIER PANEL SESSION TRYING TO DO MORE TO CONNECT PRE-CLINICAL MODELS OF PARKINSON'S TO CLINICAL TRIAL ASSESSMENTS OR OUTCOME MEASURES WE USE, WE STRUGGLE WITH THAT A LOT HOW TO TICKET THAT GAP IN THE TRANSLATIONAL -- FIX THAT GAP IN THE MINE AND ONE THING IS TO USE VIDEO OR SCREEN TECHNOLOGY THAT BOTH MOUTH SPECIES AND HUMANS CAN DO TO SEE IF WE CAN MAKE THE TEST MORE IDENTICAL TO UNDERSTAND BETTER WHERE WEAK SPOTS ARE, AND I DON'T KNOW IF TELEMEDICINE INITIATIVES, WHETHER THERE ARE WAYS TO THINK ABOUT THAT MORE OR IF THERE'S A ROLE IN THE AMOUNT OF NON-MOTOR SYMPTOMS OF PD THAT CAN BE INTRODUCED. >> TWO QUESTIONS. FIRST WAS ABOUT POWER CALCULATIONS FOR PRODROMAL STUDIES. AT LEAST ADDRESS SOME OF THE ISSUES THAT MIGHT BE INVOLVED IN THINKING THE COST AND EFFICIENCIES FOR CONDUCTING A PRODROMAL PD TRIAL. SECOND QUESTION IN A MINUTE IS BRIDGED ACROSS THE DIVIDE. CHRIS, ARE YOU THERE? >> YES. >> CAN YOU TAKE A CRACK AT THE QUESTION ABOUT WHAT ARE ISSUES INVOLVED IN TERMS OF LOGISTICS AND PLANNING AND POWER FOR PRODROMAL TRIAL DESIGN? >> SURE. TO CLARIFY, I'M NOT SURE IT'S UNIVERSALLY TRUE, A PRODROMAL -- FOCUSING ON PRODROMAL COHORT WILL HAVE LESS POWER. IT MAY OR MAY NOT. ONE ADVANTAGE IS SPECIFIC PRODROMAL COHORT RELATED TO TARGET ENGAGEMENT OF TREATMENT YOU'RE LOOKING AT, YOU CAN GAIN POWER BY FOCUSING ON A COHORT WHERE YOU HAVE THE EFFECT EXPECTED AS OPPOSED TO LARGER GROUP WHERE YOU MIGHT HAVE EFFECT IN SOME OF THE SUBJECTS ENROLLED IN THE TRIAL AND NOT OTHERS AND LOSE THE EFFECT LESS POWER. I THINK IN TERMS OF WHAT IS PROBABLY MORE COSTLY, IN TERMS OF PRODROMAL STUDIES IS NOT SO MUCH THE POWER ONCE YOU GET SOMEONE IN BUT THE SCREENING AND COST INVOLVED IN TRYING TO GET INDIVIDUALS INTO THE STUDY. SO I THINK THAT THEY MAYBE LESS POWER, MAY NOT BUT IT KIND OF GOES BACK TO THE POINT MADE EARLIER THAT THERE NEEDS TO BE DISCUSSION TO TIE THE COMPONENTS TOGETHER OF THE CLINICAL INPUT, THE STATISTICAL INPUT AND THE TRIAL DESIGN TO TRY TO P COME ONE THE MOST EFFICIENT FROM A STATISTICAL STANDPOINT AND OPERATIONAL STANDPOINT TYPE OF DESIGN THAT CAN BE DONE. >> SECOND QUESTION WAS OUTCOME MEASURES IF YOU BRIDGE ANIMAL MODELS AND PATIENTS. CAR LEE, WOULD YOU TAKE A CRACK AT THAT? >> I'M NOT A LOUD PERSON BUT I KNOW THAT PEOPLE HAVE TRIED TO DO SOME OF WHAT YOU'RE TALKING ABOUT ESPECIALLY LOOKING AT LOOKING AT PRIMATE MODELS AND DOING COMPARISONS WITH HUMANS. I THINK THERE IS LESS WORK THAT HAS BEEN DONE LOOK AT BEHAVIORAL EFFECTS OF OTHER MODELS LIKE GENETIC MODELS OF PARKINSONISM, THAT PROBABLY IS A GOOD IDEA AND THE APPROACH YOU'RE DESCRIBE, IDEALLY LINKING WITH SOME METABOLIC BIOLOGIC PATHOLOGIC MARKERS WOULD BE AN IMPORTANT STEP. >> THANKS. COUPLE OF QUESTIONS THAT CAME IN VIA INTERNET TO TACKLE. ONE IS ABOUT PARKINSON PLUS SYNDROMES. PATIENTS WITH PARKINSON PLUS SYNDROMES ARE GENERALLY EXCLUDED FROM CLINICAL TRIALS FOR PD. FURTHER BASIC CLINICAL RESEARCH ON SYNDROMINGS PROVIDE IMPORTANT CLUES TO THE ANATOMIC PHYSIOLOGIC AND CLINICAL QUESTIONS BEING ADDRESSED BY STUDIES ON CLASSICAL PD I FOUND NO MENTION OF PARKINSON'S PLUS SYNDROMES IN A PROPOSED AGENDA FOR FUTURE RESEARCH ON PD. IF YOU MIGHT TACKLE THIS ONE, WHERE DOES NSA ON THE ONE HAND MAYBE PST AND TVD AND THE WHOLE GALLERY OF OTHER PARKINSON'S PLUS SYNDROMES FIT BIOLOGICALLY IN TERMS OF TRIAL DESIGN INTO OUR PARKINSON'S PROGRAM? >> PERSONALLY I WAS TRYING TO BE ADVOCATE FOR A NUMBER OF YEARS TO ARGUE THAT MSA CITY NUCLEIN DISORDER LIKE PARKINSON'S DISEASE BUT HAVING A MORE RAPIDLY PROGRESSING COURSE WOULD LEND ITSELF AS MODEL DISEASE TO STUDY PUNITIVE DISEASE MODIFYING AGENTS THAT HAVE TARGET ENGAGEMENT WITH SYNUCLEIN MECHANISMS AND IF COMPANIES OR WHOEVER HAD COMPOUNDS LIKE THAT, WANT TO TEST THEM WITH CLINICALLY MEANINGFUL END POINTS LIKE DELAYING MILESTONES OF DISABILITY MSA LENDS ITSELFS AS A MODEL DISORDER. THAT'S CERTAIN CAVEATS BECAUSE THE EXACT TYPE OF SYNUCLEIN PATHOLOGY IS DIFFERENT BETWEEN THE TWO BUT BY AND LARGE WE SHOULD HAVE AN EYE ON MSA SPECIFICALLY BEING POTENTIAL MODEL DISEASE FOR EARLY CLINICAL PROOF OF CONCEPT STUDIES IF WE HAVE AGENTS WHERE WE BELIEVE THEY HAVE TARGET ENGAGEMENT WITH SYNUCLEIN. >> WHERE DO YOU SEE PST OPATHYS IN THIS? >> IT WOULD BE ACROSS THE BOARD. THEY MAYBE INFORMATIVE WHEN TRYING TO ASSESS BIOMARKERS, IMAGING BIOMARKERS FOR EXAMPLE AND TRY TO DESIGN ALGORITHMS FOR MULTI-MODAL IMAGING THAT HAS PROGNOSTIC OR PROGRESSION MARKER CAPABILITY. AGAIN, THESE DISEASES WHICH WOULD HAVE MORE CHANGE OVER TIME WOULD BE MAYBE BE GOOD MODELS TO TEST, STICK WITH IMAGING MARKERS, IN TERM OF SENSITIVITY TO CHANGE OVER TIME. >> THANK YOU. SO THIS IS ONE AUTOPSY CONFIRMATION, KAREN I'LL GIVE TO IT YOU. DURING THE FIRST PANEL DISCUSSION THERE WAS MENTION OF NEED TO FOLLOW PATIENTS TO AUTOPSY. CAN THE PANEL ADDRESS THE FACT THAT SINCE DIAGNOSIS OF PD IS ONLY 80, 90% ACCURATE DURING LIFE, IT'S DIFFICULT AND INACCURATE ANDESINE SPECIALLY DIFFICULT AND INACCURATE EARLY IN THE COURSE OF DISEASE, ONE OF THE RECOMMENDATIONS FORKING WITH SURE BIOMARKER GENETIC OR OTHER STUDIES PLAN TO VALIDATE DIAGNOSIS BY AUTOPSY SO THIS IS A QUESTION ABOUT EARLY DIAGNOSIS AND NEED TO CONFIRM VALIDITY OF BIOMARKERS VIA AUTOPSY. >> THIS SPEAKS TO THE POINT YOU NEED OBSERVATIONAL STUDIES TO FOLLOW PEOPLE TO DEATH AND YOU NEED MECHANISMS WHETHER REMOTE ACCESS OR SEEING PATIENTS REGULARLY TO FOLLOW THEM SO YOU HAVE AN EXAMINATION PRIOR TO DEATH THAT'S MEANINGFUL. WE NEED TO BETTER INTEGRATE ALL THE DIFFERENT WAYS WE GET AUTOPSIES WHETHER IT'S THROUGH ADRC OR UDALL CENTERS. WE HEARD THIS MORNING THAT STORY MENTION THERE WOULD BE A JOINT EFFORT FOR THE BRAIN BANK. DON'T KNOW HOW THAT WORKS BUT IT'S INTEGRAL TO AGAIN EDUCATE PHYSICIANS ON THE IMPORTANCE AS WELL AS PATIENTS AND WHAT IT MEANS TO PROVIDE AUTOPSIES. SO WE NEED TO INTEGRATE WITH CLINICAL TRIALS BETTER. WHICH HAS NOT HAPPENED TO THE EXTENT IT SHOULD. >> I WANT TO EMPHASIZE WHERE YOU HAVE A LONG CAREFULLY COLLECTED HISTORY OF DISEASE PROGRESSION. THAT MAY HELP GET A BETTER HANDLE ON QUESTIONS WE HAVE BEEN ADDRESSING. >> THANKS. SO LET'S GO BACK TO QUESTIONS FROM THE AUDIENCE BACK ON THE RIGHT. >> MY NAME IS RICHARD CROSS, I'M A CARE PARTNER. MY QUESTION, I OFTEN WONDER WHAT EXACTLY MY WIFE WAS -- PATIENT IS EXPERIENCING AND WHAT I -- IF I KNEW THAT I COULD PROBABLY BE MORE HELPFUL TO HER. I WONDER HOW ONE GETS A CLEAR PICTURE OF THE EMOTIONAL TEXTURE OF OFF PERIOD? ABSTRACTIONS ARE NOT VERY USEFUL DEALING WITH THAT. I THINK IT WOULD BE VALUABLE TO ME AND OTHERS INCLUDING PHYSICIANS TO KNOW WHAT PATIENTS ARE EXPERIENCING. WHAT IT FEELS LIKE. >> THANKS FOR THE QUESTION. I THINK I UNDERSTAND. I WAS THINKING WHAT PATIENT EXPERIENCE DURING NON-MOTOR OFF. >> RIGHT. EXCELLENT QUESTION. ONE OF THE REAL CHALLENGES FOR CARE PARTNERS IS ESPECIALLY IN PARKINSON'S DISEASE TO UNDERSTAND DISDISORDER WHERE THE AFFECTED PERSON IS ABLE TO DO THINGS WHERE POTENTIALLY MOMENTS LATER THEY CANNOT REQUIRES INCREDIBLE PATIENCE AND INSIGHT INTO THIS VERY CHANGEABLE DISORDER. YOU ARE QUITE RIGHT, DURING OFF TIME IT'S NOT JUST THE MOTOR FEATURES BUT ALSO EMOTIONAL FACTORS AND NON-MOTOR FEATURES THAT CAN PLAY A ROLE. I THINK THAT IT'S A VERY PROVOCATIVE QUESTION BECAUSE I DON'T THINK THERE'S BEEN ANY WORK THAT I CAN RECALL MAYBE OTHERS CAN, IN TERMS OF TRYING TO GET AT WHAT IS THE EXPERIENCE OF OFF TIME BEYOND THE OFF INABILITY TO MOVE. I DON'T KNOW IF OTHERS HAVE ANY INSIGHT INTO THAT. BUT THANK YOU FOR BRINGING IT UP. >> DOES THAT ANSWER YOUR QUESTION? (OFF MIC) >> VERY INTERESTING COMMENTS. >> I LOVE YOUR IDEA OF PARKINSON'S STORIES. WHAT IT BRINGS TO MIND FOR ME IS THE DIFFERENCE BETWEEN A LOT OF WHAT WE'RE TALKING ABOUT TODAY IN TERMS OF CLINICAL TRIALS AND PERSONAL EXPERIENCE AND INDIVIDUALIZED EXPERIENCE. I THINK THAT IS YET ANOTHER CONUNDRUM WE HAVEN'T QUITE GRAPPLED WITH CLINICAL TRIALS BY NECESSITY PRODUCE DATA ACROSS THE ENTIRE POPULATION AND VERY OFTEN MISS, DOESN'T CAPTURE INDIVIDUAL EXPERIENCE. IT'S AN IMPORTANT POINT. >> SO WE'RE RUNNING OUT OF TIME, MAYBE TIME FOR THREE MORE QUESTIONS, OVER THERE FIRST. >> (INAUDIBLE) UNIVERSITY OF MICHIGAN. BRIEF COMMENT WITH RESPECT TO NUMBER 2, I AGREE COMPLETELY WITH THE IMPORTANCE OF FOCUSED ON PRODROMAL PD AND THERE IS SOMETHING PRODROMAL PD. THE WAY THAT'S CONSTRUCTED CURRENTLY IS THAT IT SORT OF GIVES THE SENSE WE KNOW WHAT PRODROMAL PD IS. AND UNDERNEATH THIS IS INCREDIBLE INFLUENCE OF THE IDEA WHICH MAY OR MAY NOT BE ACCURATE. WHICH IS REM BEHAVIOR DISORDER WHICH IS PREDICTIVE, THINGS LIKE CONSTIPATION AND SO FORTH ARE VERY MUCH UNCLEAR. IT'S JUST THE IMPORTANT, CONSTRUCTIVE, LINGUISTIC POINT TO CRITICALLY TEST THESE AND I THINK THAT WHOLE COP SEPTEMBER THERE ARE A LOT OF QUESTIONS DEBATING THAT. BUT THAT'S IMPORTANT. WE DON'T WANT TO ALARM PATIENTS WHEN PEOPLE HAVE 50 A CHANCE THEY'LL GET PARKINSON'S BECAUSE WE REALLY DON'T KNOW THAT. IT SHOWS INCREDIBLE NEED FOR SYNUCLEIN AGENT THAT'S THE THING THAT'S LACKING HERE SO I JUST LEAVE IT AT THAT. >> WE AGREE. WE CERTAINLY AGREE WITH INTEREST IN THE IMAGING AGENT. >> HOWARD (INAUDIBLE) PHILADELPHIA. ONE OF THE BIGGEST RISK FACT DOORS FOR DEVELOPING PARKINSON'S DISEASE HA HASN'T BEEN DISCUSSED IS AGING. BILL, DO YOU GET MORE LIKELY, IF THE POPULATION LIVED LONG ENOUGH MAYBE EVERYBODY WOULD DEVELOP PARKINSON'S DISEASE. WOULD THE PANEL CO-MORE BITTY THIS IS OCCUR WITH AGING AS POSSIBLE RISK FACTORS? FOR EXAMPLE DAVID IRWIN AT PENN DID A STUDY OF 120 PATIENTS WITH AUTOPSY BASED STUDY WITH PARKINSON'S DISEASE, COLLABORATION BETWEEN UNIVERSITY OF WASHINGTON AND ONE SIGNIFICANT BUT COVERED UP RISK FACTORS WAS VASCULAR DISEASE OF THE BRAIN. SO THAT IS SOMETHING I'M THROWING OUT FOR YOUR COMMENTS. >> ANYONE LIKE TO TACKLE THAT ONE? PARTICULARITY THE CO-MORBID INTERACTION OF VASCULAR DISEASE CERTAINLY IN ALZHEIMER'S DISEASE, >> CERTAINLY IN A HETEROGENEITY IN PARTICULAR THE VASCULAR COMPONENT HOW MUCH THAT EFFECTS LOWER BODY PARKINSONISM AND GREATER RISK OF COGNITIVE IMPAIRMENT, THOSE ARE QUESTIONS THAT HAVE BEEN ADDRESSED. YOU MAKE A IMPORTANT POINT ABOUT CO-MORBID CONDITIONS AND AGING, MAYBE I'M JUST OPTIMISTIC BUT I DON'T THINK THAT PARKINSON'S IS THE INEVITABLE OUTCOME IF YOU LIVE TO BE 200 FOR EVERY HUMAN BUT OBVIOUSLY AGE IS A CRITICAL FACTOR. TO WHAT EXTENT IS AGE RELATED CONDITION OR PASSAGE OF TIME AFTER TRIGGERING INSULT OR INSULTS REMAINS TO BE UNDERSTOOD. >> YOUR COMMENTS MADE ME THINK ANALOGY BUT WHAT WE TALKED BEFORE ABOUT BIOMARKERS AND CLINICAL MANIFESTATIONS HERE, WHEN WE THINK COMORBIDITIES BECAUSE THERE'S CO-MORBID FACTORS THAT HAVE BIOLOGICAL BEAR ACTION BUT WE ALSO KNOW LITTLE ABOUT THE INTERACTION OF VARIOUS MEDICAL COMORBIDITIES PERIOD. WE UNDERSTAND THE INDIVIDUAL WHO HAS PARKINSON'S DISEASER THREE AT THIS, IS OBESE, SO FORTH, IS LIKELY GOING TO HAVE A MUCH WORSE COURSE THAN THE FIT PERSON SO FORTH BUT THAT'S ALSO AN AREA RELATIVELY UNDERSTOOD STUDIED. >> A >> THANK YOU. I HAVE A COMMENT AND QUESTION FOR THE PANELISTS TO DISCUSS ABOUT, HOW YOU SEE POTENTIAL VIEWS OF ANIMAL MODELS TO HELP ADDRESS ESSENTIALLY WHAT WE TALKED ABOUT THIS MORNING WHICH IS A VERY DIFFERENT FROM WHAT WE HAVE BEEN DOING IN THE LABORATORIES OVER THE PAST MANY YEARS DEALING WITH DOPAMINE DEPLETION PROBLEMS IT'S CLEAR IN THE FIELD OF PARKINSON'S, WE HAVE BEEN A LITTLE BIT PRIVILEGE IN A WAY OF DEVELOPING GOOD THERAPIES BECAUSE OF THE LINK BETWEEN NIGRAL STRIATAL DEPLETION. SO WE'RE GOING BACK TO CASE ONE BECAUSE THE PROBLEMS THAT WERE RAISED HERE H MORNING, EITHER DURING THE PRODROMAL PHASE OR NON-MOTOR SYMPTOMS THE BOTTOM LINE IS THAT WE KNOW LITTLE ABOUT THE PATHOLOGY, PATHOPHYSIOLOGY OF DISEASE DISORDER IN PEOPLE ESSENTIALLY, THIS IS NOT CLEAR. AND SO THE QUESTION IS, HOW DO WE GO BACK TO THE LAB AND TRY TO -- AND I THINK TO ADVANCE THOSE AS WE HAVE SEEN FOR THE MOTOR SYMPTOMS WE WILL NEED GREAT RELIABLE MODELS THAT CLEARLY PARKINSON'S FEATURES, BECAUSE THE PROBLEM IS THAT MANY OF THESE FEATURES CAN BE INDUCED IN DIFFERENT WAYS WHICH HAVE NOTHING TO DO WITH P&A DISEASE. SO I DON'T KNOW IF THAT'S AN ANSWER TO THAT BUT'S AN IMPORTANT POINT WE NEED TO DISCUSS AND MAYBE WE NEED TO GO BACK TO THE PATHOLOGY OF THE BRAIN OF PD PATIENTS AND ANALYZE NON-DOPAMINERGIC PATHOLOGY. IT'S A VERY IMPORTANT ISSUE BECAUSE IF NOT WE MAY CLEARLY REALLY DEVIATE A LOT OF THE BASIC RESEARCH TOWARDS DIFFERENT AVENUES WHICH MAY THINK WE ARE DEALING WITH WHAT IS REALLY A SYMPTOM OF PARKINSON. THIS IS INDUCED BY DOING DIFFERENT MANIPULATION WHICH HAVE NOTHING TO DO WITH PARKINSON'S. SO IF YOU CAN SOMEONE CAN COMMENT ON THAT. >> THAT WAS INCREDIBLY GOOD SEGUE TO THE NEXT SESSION WHICH IS GOING TO BE ON TRANSLATIONAL PIPELINE, THIS MEETING IS ABOUT BUILDING BRIDGES BETWEEN CLINICAL AND TRANSLATIONAL AND BASIC RESEARCH. WONDERING IF SOMEBODY ON THE PANEL MIGHT JUST ON THAT OR COVER IT APPROPRIATELY. HE DID. THANK YOU VERY MUCH, EVERYONE. >> LET'S THANK OUR PANEL. [APPLAUSE] >> WE'RE JUST A FEW MINUTES BEHIND SCHEDULE SO WE'RE GOING TO TAKE ALMOST AN HOUR BREAK FOR LUNCH AND RECONVENE AT ONE O'CLOCK. THANK YOU ALL VERY MUCH. SO OUR SECOND SESSION, BUILDING A TRANSLATIONAL PIPELINE FOR PARKINSON'S DISEASE THERAPEUTICS IS LED BY JOHN DONE LAP, -- DUNLOP, STEVEN FINKBEINER AND MARGARET SUTHERLAND AND HAO WANG. THANK YOU FOR COMING BACK. STEVE. >> TERRIFIC. IT'S MY PLEASURE TO BE HERE. I WANT TO ALSO SET ME THANKS TO STORY LANDIS AND TO THE NINDS CREW, KOROSHETZ TOM MYRICK AND HOW FOR ASSEMBLING THIS GROUP. JOHN MY CO-CHAIR OUR FOCUS IS TRANSLATION. I WANT TO DEFINE IT FOR PURPOSES OF THIS DISCUSSION. WHAT WE'RE TALKING ABOUT IS THE PROCESS BY WHICH WE TAKE BASIC SCIENCE DISCOVERIES, EEL HEAR MORE TOMORROW MORNING ABOUT THE BASIC SCIENCE GROUP ALL THE WAY TO THE POINT WE HAVE EFFECTIVE MEDICINES FOR PEOPLE WITH PARKINSON'S DISEASE. WE'RE CHIEFLY CONCERNED WITH THIS PROCESS, BRINGING THINGS FROM DISCOVERY TO MEDICINE IN THE CLINIC. THE PROBLEM OUR GROUP FOCUSED ON IT IN TRANSLATION FOR PARKINSON'S DISEASE, THE SUCCESS RATE OF WHAT WE HAVE ALREADY FOR TRANSLATIONAL PIPELINE IS VERY LOW. NEURODEGENERATIVE DISEASE INCLUDING PARKINSON'S IS TIED FOR THE LOW, 7% SUCCESS RATE FROM CLINICAL TRIAL NEUROLOGICAL DISEASE TO APPROVED MEDICINES. THAT HAS HUGE IMPLICATIONS THE COST OF CLINICAL TRIALS IS HIGH SO COMPANIES HAVE TO PLACE BIG BETS ONLY TO FAIL LATENT PHASE 3 TRIALS, IT'S DISCOURAGING, I HEARD A TALK FROM RICHARD RESNICK THAT I THOUGHT WAS INTERESTING, HE CALCULATED SOCIETAL COSTS OF DISEASES, DIABETES, HEART DISEASE, ONCOLOGY NEURODEGENERATIVE DISEASE AND THE AMOUNT PHARMA INVESTED AND THE NUMBER OF PROGRAMS THAT EXIST. BY THAT ESTIMATE PHARMA UNDERESTIMATE -- INVESTED BY 2 TO 10 TIMES BASED ON SOCIETAL NEEDS IN TERMS OF WHAT IS NECESSARY FOR DEVELOPING THERAPIES. BUT FROM A BUSINESS STANDPOINT IT MAKES SENSE IT'S JUST A RISKY AREA TO DO WORK IN, IT'S HARD TO JUSTIFY MAKING THAT ADDITIONAL INVESTMENT. WHAT YOU'LL HEAR FROM OUR TRANSLATIONAL GROUP IS A FOCUS ON WHAT WE CAN DO TO FIX THIS LEAKY PIPELINE FAILURE AT EACH STAGE PROCESS OF TRANSLATION ULTIMATELY WITH FEW MEDICINES TO OFFER TO PATIENTS. SO HOW TO FIX PIPELINE AND WITH SOME FOCUS ON WHAT SHOULD WE PUT IN THE PIPELINE. AS IF WE NEEDED TO UNDERSTOOD SCORE FURTHER, WE DON'T NEED TO HAVE A DISEASE MODIFYING FOR THIS CONSEQUENCE SO THIS NEEDS TO BE ADDRESSED. WE HAVE A TERRIFIC GROUP OF PEOPLE WHO ARE PART OF OUR TRANSLATIONAL COMMITTEE WE PICKED A GROUP WITH DIVERSION PERSPECTIVES. SO WE BROUGHT PEOPLE HAVE ACT DEEM WHERE TO TALK ABOUT INNOVATION THAT ARISES THERE BUT ALSO KEY PEOPLE FROM PHARMA WHO CAN BRING PERSPECTIVE ON REAL WORLD DIFFICULTIES OF MOVING THESE FORWARD IN PERSPECTIVES AND ISSUES THAT NEED TO BE ADDRESSED. WE INVITED PEOPLE WHO HAVE DEEP EXPERTISE IN PARKINSON'S DISEASE WHO WORKED IN THE FIELD A LONG PERIOD OF TIME AND OFFER THAT IMPORTANT PERSPECTIVE IN ADDITION BROUGHT PEOPLE WITH DIFFERENT APPROACHES OR WHO HAD SUCCESS FROM DIFFERENT AREAS TO CROSS FERTILIZE PARKINSON'S DISEASE WITH SUCCESSES IN SOME OTHER AREAS OF NEURODEGENERATIVE DISEASE. WE HAD A SERIES OF TELECONFERENCES TO FORMULATE DEBATE AND REFINE PROPOSED RECOMMENDATIONS, WE RANKED TEN MAW YOUR RECOMMENDATIONS FROM THE GROUP AND WE HAVE NOW DIVIDED THOSE TEN INTO FOUR TOPICS THAT YOU'RE GOING TO HEAR AFTER I SPEAK. ONE IS EARLY IN THE PIPELINE. IT FOCUSES ON TARGET IDENTIFICATION, VALIDATION. WE HAD THREE RECOMMENDATIONS IN THIS AREA. WE WANTED TO DO THOROUGHLY UNDERSTAND TARGETS AND PATHWAYS THAT OVERLAP WITH WHAT YOU HEAR FROM THE BASIC SCIENCE GROUP BUT FROM OUR GROUP SPECIAL EMPHASIS ON TARGETS THAT HAD GENETIC VALIDATION FROM HUMANS. AGAIN TRYING TO CONNECT WHAT WE DO IN TRANSLATION TO SOMETHING DATA FROM PEOPLE, CLINICAL TRIALS. ONE AREA OF TRANSLATION WHICH YOU'LL SEE COMMONLY IN TOMORROW'S TALK AND YOU HEARD TODAY IN THE CLINICAL GROUP WAS FOCUS ON ALPHA SYNUCLEIN, MISFOLDING IN CONNECTION OF MITOCHONDRIA, THE VIEW OF TRANSLATIONAL GROUP HAS RISK TO A POINT WHERE IT WARRANTS TO A FOCUS ON ITS OWN AS A AREA FOR TRANSLATION. MEASURING PATHWAY ARCHITECTURE AND PARKINSON'S DISEASE, IN THIS CASE REALLY BRINGING A SYSTEMS APPROACH. CONCEPT OF MAL ADAPTIVE PLASTICITY. THAT'S DIFFICULT TO THINK ABOUT UNLESS WE HAVE TOOLS TO BE ABLE TO UNDERSTAND THE PATHWAYS AND HOW THEY ENTERRELATE AND RELATE OVER TIME. SO ONE RECOMMENDATION OF THE TRANSLATIONAL GROUP IS TO BRING MORE SOPHISTICATED TOOLS THAT WE CAN INTEGRATE TO A SYSTEMS UNDERSTANDING OF THE PROCESS. WE HOPE WE CAN PLUG LEAKS INTO THE EARLY END OF THE PIPELINE. FOCUSING ON TARGET ENGAGEMENT AND EFFICACY. YOU HEARD AGAIN FROM TALKS THIS MORNING ABOUT PET IMAGING AGENTS TO ASSAY FOR ALPHA SYNUCLEIN BURDEN AND DRUG EFFICACY THAT CAN GIVE EARLY FEEDBACK ABOUT PUNITIVE EFFICACY OF A PARTICULAR AGENT. BEFORE WE INVEST LARGE AMOUNT OF MONEY FOR PHASE 3 TRIALS. I WANT TO TAKE THIS OPPORTUNITY TO SAY FOR TARGET ENGAGEMENT AND BIOMARKERS, WE REALLY MAKE TWO DISTINCTIONS SO YOU HEARD ABOUT STATE MARKERS THIS MORNING ALPHA SYNUCLEIN BURDEN. BUT JUST AS IMPORTANT ARE MARKERS THAT WILL TELL WHETHER THE DRUG WE DEVELOP ACTS ON THE TARGET WE INTENDED TO ACT. SO IF WE DEVELOP A DRUG FOR AUTOPHAGY WE NEED TO BE ABLE TO MAKE SURE IT STIMULATES AUTOPHAGY IN THE BRAIN AT LOCATION WE THINK IT NEEDS TO BE EFFECTIVE. THAT IS PARKINSON'S PATIENTS OR NOT BUT IT'S IMPORTANT TO HAVE THAT TO BE ABLE TO KNOW THAT WE HAVE TESTED THE HYPOTHESIS WINCE THE CLINICAL TRIAL IS DONE. AS IMPORTANT ATTRIBUTES OF PUNITIVE DRUG TARGETS JUSTIFY ADVANCEMENT. BEING ABLE TO CONSTRUCT CLINICAL TRIALS AND STEPS ALONG THE WAY TO MAKE SURE IMPORTANT TO JUSTIFY MOVING DRUGS FORWARD AND MAKING THE INVESTMENTS NECESSARY. STEPPING BACK ABOUT THIS PROCESS OF TRANSLATION, BEING ABLE TO DEVELOP MODELS TO TRANSLATE FORWARD DIRECTION, THE WAY WE THINK ABOUT IT, SO THINGS WHERE IF WE GET A POSITIVE RESULT IN SIMPLER MODEL THEY WARRANT MOVING TO MORE COMPLEX COSTLY MODELS BUT HARVESTING THE DATA WE COLLECT FROM CLINICAL WORK AND FROM OUR LATER STAGE WORK TO BE ABLE TO GO BACK AND ASK ARE THEY VALID. WE HAVE A SUBSTANTIAL FAILURE RATE AND BEING ABLE TO TRANSLATE POSITIVE RESULTS FROM PRE-CLINICAL MODELS TO PRE-CLINICAL TRIAL RESULTS. ONE FOCUS IS DEVELOPING RESEARCH TOOLS WHERE THE FOSSAS IS NOT JUST MODELS BUT PAY ATTENTION TO PREDICTIVE VALUE FOR CLINICAL TRIAL RESULTS. ANOTHER AREA TO COME UP WITH STANDARDIZED PRE-CLINICAL ASSESSMENT FOR PARKINSON'S DISEASE AND ALPHA SYNUCLEIN MODULATING AGENTS. THE CONCERN IS DIVERSITY OF MODEL, APPROACHES BUT TO BE ABLE TO PROVIDE SOME ADVICE IN THE COMMUNITY ABOUT WAYS TO BE ABLE TO EVALUATE AGENTS IN A WAY TO ALLOW US TO COMPARE DATA ACROSS STUDIES. THEN THE LAST POINT ONE OF THE HIGHEST RECOMMENDATIONS WE HAVE WAS TO REALLY ASK QUESTION IS PARKINSON'S DISEASE ONE DISEASE, MANY DISEASES, WHAT MORE CAN WE DO TO STRATIFY PATIENTS TO HELP US BECOME MORE SUCCESSFUL WITH CLINICAL TRIALS? YOU HEARD A BIT ABOUT THIS THIS MORNING. PERSPECTIVE FROM JOHN DUNLOP IN A MINUTE ABOUT THIS ISSUE. AS RELATES TO TRANSLATION. INTEGRATED DATABASES. THIS IS A RECOMMENDATION THAT SHOWED UP IN ALL THREE GROUP, CLINICAL GROUP TRANSLATION AND BASIC SCIENCE GROUP. WE ARE INTERESTED TO TRY TO USE THE DATABASES, CLINICAL DATA AND DATA FROM PRE-CLINICAL MODELS TO FOCUS ON THAT TRANSLATION PROCESS. COMING UP WITH BETTER THINGS TO FOCUS ON AS THE KEY PHENOTYPE WE NEED TO BE ABLE TO KNOW WHETHER WE'RE TRANSLATING OR NOT SO WITH THAT I WOULD LIKE TO TURN OVER MY SESSION TO JOHN WHO WILL BEGIN WITH RECOMMENDATIONS TO BUILDING TRANSLATIONAL PIPELINE FOR PARKINSON'S DISEASE THERAPEUTICS WITH FOCUS ON PATIENT AND DISEASE STRATIFICATION. THANKS VERY MUCH FOR SETTING UP THE SESSION. GOOD AFTERNOON, PLEASURE TO BE HERE. WHAT I WOULD LIKE TO DO IS JUST START OFF WITH A SLIDE FROM A PRESENTATION U USED A NUMBER OF TIMES, I THINK SPEAKS TO THE ISSUES WE HAVE BEEN DISCUSSING THIS MORNING AROUND CHALLENGES NOT ONLY CHALLENGES AS FAR AS PARKINSON'S DISEASE BUT ALSO NEUROSCIENCE DRUG DISCOVERY IN GENERAL. THAT RELATES TO SCIENTIFIC CHALLENGES AROUND BIOLOGY COMPLEXITY OF THE DISEASES OR SOMEWHAT RUDIMENTARY UNDERSTANDING OF THE FUNDAMENTAL PATHOPHYSIOLOGY OF THE DISEASE, CHALLENGE OF BLOOD BRAIN BARRIER, ANIMAL MODEL AND PREDICTIVE VALUE, IF YOU WANT TO GET REAL IN NEUROSCIENCE DRUG DISCOVERY WE CAN'T CONTINUE TA TAKE THINGS INTO CLINICAL TRIALS WITHOUT GOOD MARKERS FOR CONFIRMING TARGET ENGAGEMENT TARGET ACTIVITY. CLINICAL CHALLENGES WE HEARD THIS MORNING AND OBVIOUSLY ONE THING THAT'S VERY CLEAR LOW PRODUCTIVITY STEVE HIGHLIGHTED ALONG HIGH COST SO BIC CHALLENGE HERE. ONE THING TOM MENTIONED IN HIS INTRODUCTION WAS BY DEFINITION WE WERE BROKE INTO THREE WORK STREAMS ONE AT BASIC BIOLOGY, ONE AT TRANSLATION, ONE AT THE CLINICAL SPECTRUM OF THINGS IN PRACTICE WITH INTEGRATE THINKING VERY MUCH IN HORIZONTAL OPPOSED TO VERTICAL DIMENSION. DEFINING THE ATTRIBUTES THAT WE BRING INTO THE TRANSLATIONAL PIPELINE, WE THINK THE EARLIEST MINUTE NOT ONLY HOW TO DEVELOP A SMALL MOLECULE THAT MODULATES THE TARGET BUT ALSO DEVELOP THE REQUISITE SET OF BIOMARKERS AND TOOLS TO MAKE SURE WE TEST THE MECHANISM IN THE CLINIC. SO THE TWO MAIN RECOMMENDATIONS THAT CAME OUT OF THE GROUP PATIENT DISEASE STRATIFICATION SHOWN HERE. I DON'T THINK I NEED TO READ BOILERLY ONE IS AROUND HOW WE DO A BETTER JOB OF REMOVING SOME OF THE HETERO GENEITY IN CLINICAL TRIALS RIGHT NOW FOR PARKINSON'S AND THE SECOND WHICH WAS OBVIOUSLY BOTH ENDED UP BEING COMMON THEMES ACROSS THE BASIC TRANSLAGGAL AND CLINICAL PROGRAM, THAT HIGHLIGHTS THE IMPORTANCE TO ALL OF US AND NOT ONLY PD RESEARCH BUT RESEARCH FOR NEURODEGENERATIVE DISEASE IN GENERAL. BUT I WILL LIKE TO TALK ABOUT THIS DEFINITION OF TRANSLATION AND STEVE DESCRIBE AND SHOWED A LEAKY PIPELINE. THIS IS THE CLASSIC DRUG DISCOVERY PROCESS. YOU SAW SOME OF THIS EARLIER ON IN THE CLINICAL SECTION WHERE WE'RE FOCUSED -- I APOLOGIZE FOR THAT. JUMPING AHEAD OF MYSELF. BASICALLY WE'RE TALKING TRANSLATIONAL PLACE HERE FROM BASIC FINDINGS WHICH COME OUT OF PREDOMINANTLY ACADEMIC LABS NEW SCIENCE FINDINGS, DELAYED STAGE WHERE WE HAVE TO RAMP TO PIVOTAL CLINICAL TRIALS, AND IN THE STAGE IN BETWEEN DEVELOPING MOLECULES TRYING TO TAKE THE BASIC FINDINGS ALL THE WAY TO EARLY CLINICAL STUDIES TO GIVE CONFIDENCE WHETHER WE MIGHT HAVE FUTURE DRUG THAT MIGHT TREAT PATIENTS. THE QUESTION IS WHERE DO CHALLENGES LIE. THE REAL ANSWER IS CHALLENGES LIE EVERYWHERE. UNPLUG THE LEAKY PIPELINE FROM TARGET ID AND VALIDATION TO CLINICAL DEVELOPMENT. I THINK WE HAD THE DAYS IN THE PAST AND PHARMA I CERTAINLY REMEMBER MOLECULES THAT DON'T DO ANYTHING AND THE PRE-CLINICAL WOULD SAY WE GAVE NICE MOLECULES TO THE CLINICAL GUYS AND THEY DON'T KNOW HOW TO MAKE THEM INTO DRUGS. IT'S NOT POINTING FINGERS, THE SYSTEM NEEDS FIXING THROUGH THE PROCESS. WHAT I MEAN TARGET SELECTION IS FAR TOO LENIENT, WE'RE ALLOWED TO ENTER. WE MAY TAKE COMPOUNDS AND WE DON'T KNOW THE MECHANISM OF ACTION OF COMPOUND. SUGGESTION SYCESFUL, THAT NEEDS TO STOP PERIOD. TARGET SCREENING, I THINK WE WERE SEDUCED PROBABLY APPROPRIATELY BY THE PROMISES OF HIGH THROUGH PUT SCREENING. EXPRESS TARGETS SINGLE CELL AND WIDE SCREENINGS. THAT TAKES THE TARGET OUT OF ANY PHYSIOLOGICALLY RELEVANT CONTEXT SO NOT BASHING HIGH THROUGH PUT SCREENING, I HAVE BEEN A STRONG SUPPORTER OF IMPLEMENTATION AND -- IN MY ROLE WITHIN PHARMA. WE HAVE COME TOO FAR RELEVANT SCREENS MAY NOT BE MORE INFORMATIVE. TARGET VALIDATION, WE'LL HEAR FROM MIKE ABOUT ANIMAL MODELS AND STANDARDIZE AND SYSTEMATIZE USE OF ANIMAL MODELS. I THINK THERE'S A VALUABLE ROLE FOR ANIMAL MODELS IN THE DRUG DISCOVERY PIPELINE BUT THERE'S ONLY SO MUCH WE CAN LEARN FROM RODENTS ABOUT THE PATHOPHYSIOLOGY OF THESE VERY, VERY COMPLEX DISEASES LIKE PARKINSON'S DISEASE IN HUMANS AND IMPRESS UPON THE NEED TO STUDY HUMANS AS MUCH AS WE CAN AS EXPERIMENTAL SPECIES. WE TAKE THAT COOKIE CUTTER STANDARD APPROACH AND CLINICAL PROGRAM REALLY HAVEN'T EVOLVED TO KEEP UP WITH OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF THE DISEASE SO THE PROBLEM LIES EVERYWHERE. HERE IS WHERE WE NEED TO GO. WHERE IS IT TAKING US? BEFORE WE HAD TARGET ID ON SOLELY ANIMAL DATA. WE NEED TO REQUIRE HUMAN DATA THAT SUPPORTS THAT PREMISE BEFORE WE MOVE TARGETS TO THE TRANSLATIONAL PIPELINE. SCREENS ARE DONE QUICKLY. WE NEED TO THINK ABOUT THE TYPES OF SCREENS WE CAN DO. WE'LL HEAR IPS CELLS L LATER. I'M NOT SAYING THE IPS CELLS WILL BE THE SAVIOR OF THE DAY BUT I THINK THEY'RE VERY VALUABLE TOOLS WE NEED TO STUDY AN DETERMINE WHETHER UTILITY IS GOING TO BE BECAUSE WE CAN STUDY IN A HUMAN CONTEXT. WE WERE VERY,VERY HEAVILY DEPENDENT ON ANIMAL BEHAVIOR, THE END POINTS THAT GAVE US CONFIDENCE THAT DRUGS WERE DOING USEFUL THINGS. WE NEED TO MOVE AWAY FROM THERE INTO MUCH MORE DEEPER UNDERSTANDING WHAT THESE COMPOUNDS ARE DOING AT THE CIRCUIT LEVEL IN TERMS OF MODIFYING WHAT THEY'RE DOING IN THE BRAIN AND RELY LESS ON BEHAVIOR. OFTEN TIMES WE USE NORMAL ANIMALS, WE KNOW SEEING LESION ANIMALS AND SO ON THIS IS HAPPENING. WE TEND TO DEFAULT TO ONCE DAILY DOSENING OUR THINKING HOWEVER YOU MIGHT WANT TO DEVELOP PRODUCTS IN THE CLINIC AND DIFFERENT DOSING RANGES FOR DIFFERENT DRUGS. THE PAST THE TARGET WAS OPTIMAL. TARGET ENGAGEMENT NEEDS TO BE OBLIGATORY BEFORE WE ADVANCE MOLECULES TO CLINICAL DEVELOPMENT. BEFORE SOMETIMES WE KIN KNOW THE MECHANISM OF ACTION OF THE DRUG, THAT'S JUST UNFORGIVABLE AND WE HAVE TO STOP OTHERWISE WE'LL HAVE MORE FAILURES IN DRUG DEVELOPMENT. WE NEED TO UNDERSTAND THE MECHANISM WHICH THESE DRUGS ARE ACTING. EVEN KNOWLEDGE IN THE PATIENT POPULATION IS OPTIONAL. WE NEED TO EXPLORE THE BIOLOGY OF THE PATIENT AND WHAT IT CAN TELL SO WE CAN FEED IT BACK TO THE TRANSLATIONAL FLOW. SOMETIMES YOU SHOULDN'T JUST WALK AWAY AFTER INITIAL PHASE 2 FAILURE. YOU NEED TO UNDERSTAND WHY DID YOU TEST THE MECHANISM, CAN YOU LEARN AND GO BACK AND IT RATE AND BACK IN WITH A BETTER STUDY SO REPEAT THE EXPERIMENTS OR DO EXPERIMENTS DRIVEN BY DATA. COUPLE OF SLIDES ON THIS CONCEPT OF PILLARS OF DRUG SURVIVAL. THIS IS BORROWED FROM A PAPER PUBLISHED FROM SOME OF MY EXPFIZER COLLEAGUES AN DESCRIBES THREE FUNDAMENTAL PRINCIPLES WE NEED TO APPLY AS WE MOVE TARGETS TO THE CLINIC. ONE IS MEASUREMENT DRUG EXPOSURE OF TARGET STATE OF ACTION. WE NEED TO BE ABLE TO MEASURE AT THE RIGHT TARGET TO EXPECT IT TO HAVE ACTIVITY COMMENSURATE WITH WHAT YOU EXPECT IT TO DO. BINDING PHARMACOLOGICAL TARGET. WE AGREE TARGET OCCUPANCY IS NEEDED TO ELICIT SOME KIND OF EFFECT. MEASURE DOWNSTREAM WHAT HAPPENS WHEN THAT MOLECULE -- DOWNSTREAM FUNCTIONAL MODULATION TELLS YOU THE P COMPOUND IS DOING SOMETHING YOU EXPECT IT SHOULD DO BASED ON MECHANISM OF ACTION AND THE TARGET HUMAN POPULATION. YOU MAY LOOK AT THESE AND SAY THAT SEEMS VERY STRAIGHT FORWARD AND WHY WOULDN'T WE BE DOING THAT. THE SHOCKING ANSWER IS WE WEREN'T AND WE PROBABLY AREN'T STILL SYSTEMATICALLY DOING THIS AND I WOULD ARGUE THIS IS SOMETHING TO CONTINUE TO IMPROVE UPON. WHAT DOES THIS MATRIX LOOK LIKE SNAP IF YOU FULFILL ALL THREE PILLARS MOST COMPANIES HAVE THESE, PFIZER HAS THREE PILLAR, ASTRA ZENECA IS FIVE Rs, OTHER COMPANIES CALL DIFFERENT THINGS BUT CLEARLY IF YOU SATISFY ALL THESE FUNDAMENTAL PRINCIPLES IN THAT TOP RIGHT HAND CORNER YOU HAVE THE MAXIMUM CONFIDENCE TRANSLATION OF THE DRUG EXPOSURE AND THE PHARMACOLOGY AND YOU WILL TEST THE MECHANISM SO IF YOU GET A NEGATIVE CLINICAL RESULT YOU CAN WALK INTO I TESTED THE MECHANISM O. DRUG AND IT DOESN'T WORK IN THIS CLINICAL POPULATION. SECONDLY IF YOU'RE IN THE SOUTH CORNER ON THE LEFT YOU HAVE SERIOUS CONCERNS IF YOU HAVEN'T SATISFIED THESE I TRIBUTES OF ABILITY TO KNOW IF A NEGATIVE STUDY WAS NEGATIVE BECAUSE YOU DIDN'T GET ENOUGH DRUG INTENDED TARGET SITE OF ACTION OR IN FACT WHETHER THE DRUG DOESN'T WORK IN THE INTENDED POPULATION. THIS IS AN EXAMPLE OF 44 PROGRAMS FROM PHASER BETWEEN 2005 AND 2009 AND NOT TO PICK ON PFIZER. IT'S A GOOD COMPANY I USED TO WORK WITH THEM, THIS IS REPRESENTATIVE OF A DATA SET FOR MOST LARGE PHARMA COMPANIES WITHIN THE TIME FRAME. THE SHOCKING REALITY IS 12 COMPOUNDS YOU CAN SEE ON THE BOTTOM LEFT HERE ENTER CLINICAL DEVELOPMENT WITHOUT ANY CONFIDENCE YOU ARE HITTING THE TARGET AND YOU HAVE A PHARMACODYNAMIC EFFECT CONSISTENT WITH DRUG MECHANISM OF ACTION. MANY DRUGS THE THAT DID HAVE ALL THAT INFORMATION CAN SHOW HERE WERE FOUND TO HAVE A HIGHER PROBABILITY OF SHOWING YOU PHASE 2 PROOF OF CONCEPT. THIS IS NOT A SEWER SCIENCE CENTRIC ANALYSIS, THIS IS ACROSS A RANGE OF THERAPEUTIC AREAS, WE ALL WANT TO BE UP IN THAT TOP RIGHT HAND CORNER OPPOSED TO DOWN BOTTOM LEFT HAND CORNER. AND THE ONLY WAY WE COTHAT IS IF WE INTRODUCE IN THIS PRINCIPLES WHICH FIRST DESCRIBED SEEMED STRAIGHT FORWARD AND YOU THINK WHY IT'S NOT A TRIVIAL MATTER TO ADOPT A PET RADIO LIGAND SO IF YOU CAN'T GET ONE DO YOU STOP THAT'S A DILEMMA AND TOUGH DECISION BUT THE CHALLENGE IS ALL A REASON TO BELIEVE BUT A REASON TO BELIEVE IS NOT ENOUGH. YOU HAVE YOU NEED GOOD DATA AND TOOLS TO BACK UP YOUR MOLECULES AN HELP SURVIVE IN CLINICAL DEVELOPMENT. SO PATIENT DISEASE STAT T JIFFYCATION SO JUST TO L COME BACK TO THAT. ONE THING I WANT TO TALK ABOUT IS ACTUALLY YOU REALLY WANT -- THIS ALSO MAY SEEM FAIRLY OBVIOUS BUT YOU WANT TO MAKE SURE YOU INCOLLIDE IN YOUR TRIALS PATIENTS WHO HAVE PARKINSON'S DISEASE. WE STILL DON'T HAVE WAYS SELECTION CRITERIA FOR TRIALS ARE TRULY WITH THE DISEASE WE OTHER TRYING TO TREAT. HOW DO YOU -- AND RELATED TO THAT, THIS GOES FURTHER GENETIC STRATIFICATION. HOW DO YOU IDENTIFY PATIENTS WITH HIGHEST PROBABILITY OF BENEFITING FROM THE MECHANISM OF ACTION ASSOCIATED WITH THE INTENDED THERAPEUTIC. SO FOR 2 MODULATOR THE FIRST PLACE YOU WANT TO GO IS INTO LOG 2 COHORT THAT WILL GIVE BEST CHANCE OF SHOWING SUCCESS. WHY IS THIS RELEVANT? IF YOU TAKE EXAMPLES FROM THE ALZHEIMER'S FIELD, WE HAVE LEARNED VALUABLE LESSONS FROM SOME OF THE ALZHEIMER'S TRIALS THAT NOW REPORTED OUT. SO BATHNUZIMAB WAS GENERATEDDED TO TEND TERMINUS AMYLOID BETA, THE BAD TOXIC PROTEIN BELIEVED TO CONTRIBUTE TO THE PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE. IT'S KNOWN LOOKING BACK IN THE THE DATA SET THAT 36% OF PEOPLE ENROLLED IN APOE TRIALS DIDN'T -- AMYLOID POSITIVITY. RECENTLY REPORTED FOR THE SOLID TRIALS MONOCLONAL ANTIBODY TARGETING THE THE CENTRAL PORTION OF A BETA. YOU PROBABLY WOULDN'T WANT TO HAVE THOSE ONE-THIRD OF PATIENTS, LET'S FORGET WHERE WE'RE TALKING ALZHEIMER'S DISEASE, IF YOU TEST AMYLOID LOWERING AGENT MAKE SURE THE PATIENTS THAT YOU HAVE IN YOUR TRIAL ARE AMYLOID POSITIVE. I THINK THE THINGS WOULD CERTAINLY APPLY TO PARKINSON'S AS WELL. SOMETHING THAT'S COME UP THIS MORNING AND WILL COME UP LATER IS THE NEED FOR ALPHA SYNUCLEIN IMAGING AGENT, THIS IS A NOT ARTICLE BY FOLKS AT FOX FOUNDATION, TRANSFORMATIONAL GAME CHANGING THE ABILITY TO HAVE THESE TYPES OF AGENTS AND I U WOULD ARGUE IT'S TRANSFORMATIONAL AND GAME CHANGING TO HAVE THESE TYPES OF AGENTS. THIS IS CLEARLY A CRITICAL NEED. WE'LL TALK MORE ABOUT THIS. BUT NOT ONLY THAT, OTHER TYPES OF ALPHA SYNUCLEIN SPECIES. WE'LL HEAR IN THE BASIC SESSION WE NEED TO KNOW WHAT THEY ARE AND MEASURE THOSE. THEY MAYBE THE THERAPEUTICALLY RELEVANT MOLECULES WE GO AFTER. TO TALK MORE GRANULARITY ABOUT THINGS WE DISCUSSED AT THE GROUP CAPTURED HERE, IDENTIFYING PROMISING BIOMARKERS FOR PATIENT STRATIFICATION. WE HEARD EXAMPLES NOW OF WHY BIOMARKERS ARE IMPORTANT. IMAGING AND BIOFLUID ASSAYS. NOVEL GENETIC AND MARKERS SYNAPTIC PROTEINS, THIS MIGHT BE FOR THINGS THAT ARE RELATED TO MECHANISMS OF ACTION. STEVE GAVE THE EXAMPLE IF WE WANT TO STIMULATE AUTOPHAGY HOW WE CAN ENSURE TO MEASURE AUTOPHAGY RELEVANT HUMAN POPULATION. DEVELOP AN UNDERSTANDING OF FACTORS CONTRIBUTING TO THE HETEROGENEITY AND PROGRESSION OF PARKINSON'S DISEASE. THE OTHER ONE THAT CAME UP NUMBER 4 HERE WAS THE DEVELOPMENT OF INTEGRATED PD DATABASE. THIS INTEGRATE DISSEPARATE DATA SETS FROM CLINICAL, PRE-CLINICAL AND PROBABLY MOST SYSTEMATIC FORM FOR THE SAME PATIENT HISTORY OF DISEASE, TREATMENT, IPS CELLS FROM THE SAME PATIENT TO RESPOND TO EXPERIMENTAL TEST DRUGS TREMENDOUSLY POWERFUL TOOLS TO HAVE THOSE. SO THAT IS MORE MY TIME IS UP SO STOP TO KEEP US ON TIME BUT I WANT TO MAKE SURE WE UNDERSTAND -- THERE ARE CLEAR FUNDAMENTAL PRINCIPLES TO THINK ABOUT TRANSLATION, ALL THE WAY FROM TARGET SELECTION THROUGH TO EARLY CLINICAL STUDIES AND WE NEED TO GET SYSTEMATIC ABOUT APPLYING THOSE. IN PARKINSON'S DISEASE DRUG DISCOVERY AND MOST SPECIFICALLY TRANSLATION. SO WITH THAT I'LL STOP THERE AND MOVE TO PAM DISCUSSION. THE PANEL DISCUSSION IS GOING TO INCLUDE MY COLLEAGUES H. STEVE, JOHN, DEAN AND I WOULD ASK THOSE GUYS TO COME UP AND JOIN US HERE PLEASE. THANK YOU. WHILE THE FOLKS ARE GETTING SETTLED, AS WE HAVE DONE IN THE OTHER PANEL SESSIONS IS START OFF BY ASKING EACH OF YOU TO ELABORATE A LITTLE BIT ON SOME OF THE COMMENTS I MADE TO SET T THIS UP BUT ALSO GIVE YOUR OWN INDIVIDUAL REFLECTIONS THAT LED US TO MAKE THESE KEY PRIORITIES FOR PARKINSON'S DISEASE TRANSLATION GOING FORWARD SO MAYBE WE'LL GO OVER TO JOHN IF YOU DON'T MIND STARTING, JOHN. >> THE THING I WOULD SAY, THE MOST IMPORTANT THING I THINK IS THE POINT YOU MADE ABOUT COLLECTING COHORTS BASED UPON GENETIC FINDINGS. WITH THE AMYLOID HYPOTHESIS IN ALZHEIMER'S DISEASE, THE DRUG TRIALS JUST ABOUT TO BE PUBLISHED IMMUNIZATION TRIALS FRUITS OF 20 YEARS OF WORK, HAY MAY OR MAY NOT BE ON THE RIGHT ROAD. IN THE EARLY 90s WE TRIED TO GET TOGETHER COHORTS OF ATP MUTATION CARRIERS AND IT WAS THOUGHT IT WOULD TAKE TOO LONG TO PUT COHORTS TOGETHER AND THEY WERE ONLY STARTED TO BE COLLECTED IN 2004. IT'S GOOD TO SEE IN MY VIEW 12 YEARS WASTED BECAUSE YOU WANT TO TEST AMYLOID THERAPIES FIRST IN AMYLOID MUTATION CARRIERS. THE POINT YOU MADE IS ABSOLUTELY ON THE NAIL, VERY IMPORTANT, IT HAS TO BE DONE FOR ALL THE OTHER -- FOR THE OTHER MUTATION CARRIERS TOO. FOR THE DOMINANT MUTATIONS WE NEED TO START TO PUT COHORTS TOGETHER FOR THOSE AS WELL. I MENTIONED IN A QUESTION THAT I THINK WE SHOULD BE PUTTING TOGETHER COHORTS OF GBA MUTATION CARRIERS FROM THE GOSHA PATIENTS. IT'S DIFFICULT AS A POINT THE APPLY THIS TYPE OF THINKING TO RECESSIVE DISEASES WHERE THEY APPEAR SPORADICALLY AND YET IN THOSE PATIENTS WE HAVE PERHAPS BECAUSE OF RICHARD'S WORK AND OTHERS WE KNOW THE MECHANISM PERHAPS BEST IN THOSE SO IN A WAY WE HAVE THE BEST OPPORTUNITY FOR MECHANISTIC THERAPIES THOSE THAT ARE THE MOST DIFFICULT TO GET COHORTS TOGETHER IN THE EARLY STAGES OF DISEASE. SO WE SHOULD BE PUTTING ENORMOUS EFFORT TO GET MUTATION SPECIFIC COHORTS FOR MECHANISTIC THERAPIES. >> MAYBE JUST SORT OF THE BRIDGE THAT, I THINK BASED ON EARLIER DISCUSSIONS WE RECOGNIZE GENETIC PZ RELATIVELY SMALL COMPONENT. THE CASE CAN BE MADE UNTIL WE HAVE A GROUP THAT SHOWS EFFICACY IT'S DIFFICULT TO ANSWER A LARGER QUESTION WILL A SINGLE THERAPY ADDRESS ALL PD PATIENTS SO THOUGH GENETIC PD MAKES A SMALL P IT OFFERS IN OUR VIEW A PATH TO DOING RIGOROUS CLINICAL TRIAL WHERE WE HAVE MORE CONFIDENCE IN THE RESULTS AND USE AGENT EFFECTIVE TO ASK THAT LARGER QUESTION WILL ALL PD RESPOND TO A PARTICULAR AGENT OR NOT. AND I THINK WE CAN ASK IT THEN IN A WAY WHERE WE HAVE SOME CONFIDENCE IN THE ANSWER SO THAT'S A REALLY KEY POINT. OTHER THING I WANT TO PICK UP ON WHAT JOHN SAID, IT SOUNDS SILLY COMPANIES WOULD SPEND HUNDREDS OF MILLIONS OF DOLLARS DOING A CLINICAL TRIAL WITHOUT KNOWING WHETHER THEIR AGENT ENGAGES THE TARGET. BUT HARDER THAN IT LOOKS. SO ONE THING FOR NIH WHICH WOULD BE VALUABLE IS TO THINK PRODLY RISK REDUCTION IN THIS AREA. TO THE EXTENT THESE TOOLS CAN'T BE DEVELOPED, THEY CAN LOWER THE RISK OF CLINICAL TRIALS IN THIS AREA IN A WAY THAT WOULD BE ATTRACTIVE TO OTHERS IF THE EQUATION MAKES MORE SENSE AND PRIVATE INVESTMENT WILL COME TOGETHER GO DOWN FARTHER. >> (INAUDIBLE) LUCKEMBURG, WHEN I HAD TO DECIDE WHETHER TO GO INTO PARKINSON'S OR NOT FOUR YEARS AGO I CHOOSE FOR PARKINSON'S BECAUSE THERE WERE MORE GENES KNOWN THAT LED TO FAMILIAL PD COMPARED TO AD. IF YOU LOOK THE LIST IS UP BETWEEN 15 AND 18 AND WHAT IT TELLS US IS THERE'S A HUGE GENETIC HETEROGENEITY THAT FALLS INTO 5, 6, 7 CLASSES AND HALLMARKS. SO JUST BECAUSE THE EXPECTATION IS WE NEED DIFFERENT STRATIFICATION, DIFFERENT THERAPIES OF PREVENTIVE STRATEGIES, WHEN YOU THINK ABOUT THIS IN TERMS OF NETWORKS, THE OTHER CONCLUSION THAT COMES OUT IS THAT WE HAVE TO -- WE SHOULD EXPECT COMBINATIONS OF THOSE. IF WE EXPECT COMBINATIONS, >> I WAS TRYING TO TELL WE ARE EXPECTING COMBINATIONS OF MECHANISMS AND WE NEED STRATIFICATION AND THAT I THINK IN PD NEXT YEAR WE EXPECT COMBINATORIAL THERAPY AS A RESULT OF THIS UNDERLYING. UNFORTUNATELY WHEN YOU ARE TALKING COMBINATIONS YOU LOSE STATISTICAL POWER, IF YOU DON'T TAKE CARE OF THE HETEROGENEITY OF YOUR POPULATION YOU LOSE YOUR THINNING OUT AVERAGING YOUR SIGNAL AND THEN YOU'RE IN TROUBLE. AS A RESULT STEVE MENTIONED THAT SYSTEMS ANALYSIS AND APPROACHES WHERE YOU TAKE CARE OF THE PATHWAYS AND MODULARITY OF NETWORKS CAN TAKE CARE OF THAT, FROM MY POINT OF VIEW THAT'S THE MOST URGENT THEORETICAL UNDERPINNING THAT WE NEED WHEN WE ARE ANALYZING AND ACTUALLY RECRUITING THE PATIENTS. WE NEED TO BE AWARE THERE'S A HETEROGENEITY POPULATION, MATHEMATICAL METHODS AND BUOY INFORMATICS AND COMPUTATIONAL METHODS TO TACKLE THOSE. THEY ARE AROUND. THEY ARE AROUND FROM CLIMATE RESEARCH, AROUND FROM MATERIAL SCIENCES, THEY ARE AROUND IN ENGINEERING INDUSTRY, AND I THINK WE HAVEN'T MADE THAT REACH OUT TO THESE KINDS OF NOW HOW AND EXPERTISE TO HELP US DESIGN TRIALS, DESIGN NEW DRUGS, IN PHARMA. >> I'M DEAN JONES, FROM THE OTHER SIDE OF THE WORLD. I HAVE MORE AN ENVIRONMENTAL SCIENTIST. SO IT IS INTERESTING THE PROGRESS HAS BEEN MADE LARGELY IN GENETICS. WE KNOW ENVIRONMENTAL EXPOSURES HAVE LITTLE CONTRIBUTION IN TERMS OF PARKINSON'S DISEASE. SO WHAT I THINK ASPECT THAT IS PARTICULARLY IMPORTANT IS THAT WE NEED AN ENVIRONMENTAL STRATIFICATION AS WELL. AS WE LEARN ENVIRONMENTAL FACTORS CONTRIBUTING TO THE DISEASE INITIATION AND PROGRESSION AND THE INTERACTION OF THOSE ENVIRONMENTAL FACTORS, THIS IS BROADLY DIETARY AS WELL AS BEHAVIORAL, INFECTIOUS WHAT WE CONSIDER THE TRUE ENVIRONMENT OF THE EXPOSURES, BUT INTERACTION WITH GENETIC FACTORS ARE IMPORTANT AND ALSO GOING TO BE VERY IMPORTANT IN BEING ABLE TO UNDERSTAND WHO WILL BENEFIT FROM WHAT INTERVENTION. I THINK THAT'S THE COMPONENT THAT I THINK IS VERY IMPORTANT IN TERMS OF STRATIFICATION, WE NEED TO BUILD TOWARD AN ENVIRONMENTAL STRATIFICATION AS WELL AS GENETIC STRATIFICATION. THE OTHER ASPECT THAT I THINK IS VERY IMPORTANT IS ONE JOHN BROUGHT UP, HAS TO DO WITH THE ISSUE OF FAILED STUDIES. THIS IS PERHAPS THE MOST IMPORTANT AS SECT INTEGRATED PARKINSON'S DISEASE DATABASES. IF WE TAKE FOR EXAMPLE THE WEATHER FORECASTING SYSTEMS, THE WEATHER FORECASTING SYSTEMS DID THE NOT ACHIEVE THEIR CURRENT CAPABILITY BASED UPON SUCCESSES THEY REALLY -- THEY DEVELOP THE CAPABILITY BASED UPON UNDERSTANDING OF FAILURES. SO I THINK THAT'S THE ASPECT SO IMPORTANT ON THE INTEGRATED DATABASES, THAT AS WE HAVE THIS WE CAN TAKE ADVANTAGE OF THE FAILURES AND UNDERSTANDING THOSE FAILURES WILL ADVANCE US TOWARD BETTER THERAPIES. >> THANKS, EVERYONE FOR EXPANDING ON THIS. I WANT TO ADD ONE MORE THING THAT KENNETH FOLLOWS UP ON STEVE'S COMMENT TO SAY RIGHTLY SO THIS WHOLE CHALLENGE TARGET ENGAGEMENT BIOMARKERS IS A DIFFICULT ONE AND I DIDN'T INTEND TO DRIVEIALIZE, THESE ARE CHALLENGING TOOLS TO GENERATE BUT I THINK THE POINT THAT NEEDS TO BE EMPHASIZED IS WE NEED TO WORK HARD TO CREATE THEM. I LIKE MANY COLLEAGUES IN PHARMA PARTICIPATED IN DECISIONS TO MOVE COMPOUNDS INTO EARLY CLINICAL DEVELOPMENT WITHOUT NECESSARILY HAVING THOSE REQUISITE MARKERS AND OFTENTIMES OTHER DYNAMICS AT PLAY THAT LEAD YOU TO MAKE THOSE TYPES OF DECISIONS. SO THINK IF WE MAKE SURE WE GET MORE SYSTEMATIC. I LIKE TO DEAN SAID QUALIFICATION OF ENVIRONMENTAL EXPOSURE, THIS IS SOMETHING YOU'RE VOCAL ABOUT DURING THE CALLS. I WANT TO REALLY DEAN YOU ARE HOT ON THE DATABASE COMMENT. DEAN PARTICULARLY AROUND INTEGRATE WITH OTHER NEURODEGENERATIVE DISEASES BUT YOU MADE A COMMENT ABOUT MAKING SURE WETRY BRING IN OTHER KEY STAKEHOLDERS, MAYBE OUTSIDE OF OUR SCIENCE, MAYBE ABLE TO HELP US. CAN YOU ELABORATE ON THAT? THEN I'LL OPEN FOR QUESTIONS OR COMMENTS FROM OTHER PANEL MEMBERS AS WELL. >> MAYBE DIRECTLY TO THIS, IF ENVIRONMENTAL FACTORS, I AGREE WITH IT, SO IMPORTANT, MAYBE WE SHOULD HAVE NIH WHY NIEHS SHOULD BE ON THE TABLE AS WELL OR CLOSELY RELATED TO TRY THE INTERNATIONAL STRATEGY TO REACH OUT TO WHERE EXPERTS ARE. WHAT I MEANT IN REACHING OUT TO ADDITIONAL SKILLS AND KNOW HOW IS THROUGH A LOT OF ENGINEERING SCHOOLS WHERE DEALING WITH NON-LINEAR COMPLEX SYSTEMS, I DON'T KNOW MORE COMPLICATED THAN BRAIN OR BODY THERE. IS A LOT OF KNOW HOW AVAILABLE HOW TO TEAL WITH THIS. WE HAVEN'T TAPPED INTO THIS. SO COMPLEX SYSTEMS, CLINICAL MEDICAL KNOWLEDGE. THAT'S THE HARD PART OF IT. WE HAVE ENGINEERS COMING TO OUR CENTER AND THEY DON'T KNOW WHAT A GENE IS. THAT DOESN'T WORK. IF WE MAKE THE REACH OUT THIS KIND OF SYSTEMS ANALYSIS, WE MAKE A STEP FORWARD. IN THIS SENSE THE TERM DATABASE INTEGRATED DATABASE MAY NOT BE THE RIGHT TERM BECAUSE IT'S NOT JUST ARCHIVE BUT MAKING SINCE AND ANALYZING IT OTHERWISE IT'S A DEAD END >> TERM THERE IS KNOWLEDGE BASE. THERE WAS A GEROSCIENCE, NATIONAL INSTITUTE OF AGING HAD A MEETING WITH SOME OF THE PARTICIPANTS THAT ARE HERE AT THIS MEETING ABOUT A MONTH AGO AND THESE ISSUES CAME UP RELEVANT TO AGE RELATED DISEASES. AND WE CAN BENEFIT BY LARK ENNOBLING BASE THAT INCLUDES -- KNOWLEDGE BASE THAT INCLUDES NEURODEGENERATIVE DISEASE BUT MORE BROADLY THIS POPULATION IS ALSO AT RISK FOR CARDIOVASCULAR DISEASE LUNG DISEASES, DIABETES, ET CETERA, SO THAT FEEDS INTO THE COMPLEXITY OF THE DISEASE PROCESS, THAT'S SOMETHING THAT -- WHERE WE CAN BENEFIT FROM HAVING SUCH A KNOWLEDGE BASE. >> STEVEN, YOU HAD A QUESTION THEN OPEN UP THE QUESTION -- >> JOHN I HAD A QUESTION FOR YOU. I THINK THIS IDEA OF TRYING TO MAKE BETTER USE OF CLINICAL TRIAL FAILURE DATA IS GOOD ESPECIALLY TRANSLATIONAL GROUP WHERE WE'RE TRYING TO REVERSE ENGINEER TRANSLATIONAL TOOLS THAT DO A BETTER JOB PREDICTING WHAT'S GOING FORWARDS. I KNOW THERE'S ATTEMPTS IN THE PAST TO TRY TO GET PHARMA INVOLVED AND BRING THE FAILURE DATA AND MAKE IT AVAILABLE TO RESEARCHERS, HAD SOME MIXED IS THERE SOMETHING NEW WE CAN DO? ANY THOUGHTS ON THAT? >> >> COUPLE OF PLACES THIS HAVE BEEN SUCCESSFUL SO THE EUROPEAN INI INITIATIVE HAS DONE A NICE JOB. MORE SO PSYCHIATRIC THAN NEAR DEGENERATIVE DISEASE BUT ACTUALLY OPENING AND SHOOTING CLINICAL DATA ACROSS COMPANIES AND ACADEMIC CENTERS. THE ONE MIND INITIATIVE IN THE U.S. IS ALSO MORE RECENTLY TAKEN THIS ON AND HAPPY EFFORTS TO DO THIS. COMPANIES LIKE LILY HAVE BEEN QUITE OPEN ABOUT GET GETTING THEIR (INAUDIBLE) DATA INTO THE FIELD AS QUICKLY AS THEY CAN. I DON'T THINK THEY NECESSARILY HELD THAT DATA BACK FOR A PERIOD OF TIME TO GET THEMSELVES ANY COMPETITIVE ADVANTAGE. ADNE ARE ENABLING TO HELP. (INAUDIBLE) IS ANOTHER EXAMPLE, DATA IS POSTED LIVE AND MANY COMPANIES ARE ACTIVELY PROVIDING FUNDING INTO THAT WITH THE KNOWLEDGE THAT THE DATA BECOMES AVAILABLE TO EVERYONE EVEN IF FUND ORGANIZE NOT. SOME COMPANIES ARE A LITTLE FURTHER ALONG THAN OTHERS GETTING THERE BUT WE'RE DEFINITELY MOVING WELL DOWN THAT PATH. >> I WAS GOING TO COMMENT ANOTHER PANEL POINT. NINDS IS WORKING WITH NIEHS TO SET UP A SEPARATE MEETING TO DEAL WITH THE ENVIRONMENTAL ISSUES AROUND PARKINSON'S DISEASE. WE THOUGHT IT NEEDED A HIGHLIGHT MAYBE JUST ON THAT. >> IN THE REMAINING FEW MINUTES WE EEL TAKE A COUPLE OF COMMENTS, QUESTIONS FROM THE FLOOR. >> THANK FOR THIS PANEL ON TRANSLATIONAL OUTREACH. I'M RICK MU LSUN. WORK IN THE PHARMACEUTICAL INDUSTRY FOR NUMBER OF OF YEARS AND WHEN WE WERE DEVELOPING MEDICINE IT WAS BASED ON CLARIFY OF BIOMARKERS AND END POINTS AND A LOT WAS BASED ON WHAT MARKET NEED FOR THE MEDICINE. AND HOW THAT AFFECTED THE COMPANY'S DECISIONS TO GO FORWARD WITH NEW MEDICINE. SO THAT'S ALWAYS FACTORS INVOLVED. IN THIS CASE I WORKED PARKINSON'S MEDICINE DEVELOPMENT BEFORE. WE DID IT AT (INAUDIBLE) I WANTED TO ASK YOU GIVEN THAT IT'S THE FDA THAT DEFINE IT IS END POINTS MEDICINES NEED TO HIT BEFORE THEY CAN BE APPROVED, THAT'S THE STATUS NOW, I DON'T KNOW IF ANYONE IS HERE FROM THE FDA, CLARITY ON BIOMARKERS AND HOW CAN WE GET BETTER DATA SO WE KNOW WHAT THE EPIDEMIOLOGY OF THIS DISEASE IS OVER TIME AND THAT INFLUENCE WHETHER OR NOT COMPANIES DECIDE TO GET INTO THIS. >> I'LL TAKE A STAB AT IT. THAT WAS BEST BY ONE CLINICAL COLLEAGUE AS WELL IF SOMEONE WANTS TO WEIGH IN. I THINK IT WAS A PRODUCTIVE DIALOGUE BETWEEN COMPANIES AND FDA TO THINK SURROGATE MARKERS UTILIZED TO HELP SUPPORT CLINICAL DEVELOPMENT AND CRITICAL THINKING GOING ON AROUND DIFFERENT TYPES OF CLINICAL SKILLS AND END P POINTS AWAY FROM THE ONES WE HAVE BEEN TRADITIONALLY RELYING ON SO YOU CAN HAVE MORE DIALOGUE IN THAT AREA, I DON'T KNOW IF WE HAVE ANYONE FROM FDA HERE BUT IT'S A GOOD PRODUCTIVE DISCUSSION THAT GOES ON. I DON'T KNOW IF ANYBODY ELSE. >> LET ME COMMENT THE BIOMARKER CONCEPT. THE CONCEPT OBVIOUSLY HAS EVOLVED OF THE YEARS AND MEANS DIFFERENCE THINGS TO DIFFERENT PEOPLE BUT FROM THE STANDPOINT OF METABOLIC BIOMARKERS WHICH ARE NOT VERY USEFUL IN TERMS OF PARKINSON'S DISEASE BUT IN TERMS OF THE CAPABILITIES, IT'S NOW POSSIBLE FOR RELATIVELY LOW COST TO MEASURE 10 TO 20,000 IN A DROP OF BLOOD. SO THERE'S -- MORE OF A METABOLIC PROFILE. THAT'S AN AREA THAT IS CURRENTLY BEING DEVELOPED AND I THINK IS GOING TO BE VERY POWERFUL FOR PROBLEMS AND SOLUTIONS AS YOU'RE SUGGESTING. >> WHAT ABOUT GETTING BETTER DATA SO THAT COMPANIES AND THE REST OF US KNOW EXACTLY WHAT'S HAPPENING WITH A PARTICULAR CHRONIC ILLNESS? ANY THOUGHTS ON HOW WE MIGHT GO FORWARD WITH THAT? OTHER THAN INCREASING THE SURVEYS THE US GOVERNMENT DOES, THAT SORT OF THING? >> >> MORE DATA IS BETTER DATAING IN MY MIND BECAUSE IT GIVES YOU INFORMATION YOU DIDN'T HAVE BEFORE SO THINGS LIKE THE PPMI INITIATIVE, PROGRESSION WHAT THE DISEASE LOOKS LIKE AND BIOMARKERS WILL LOOK LIKE OVER A COHORT OF DIAGNOSED PATIENTS, WILL BE TREMENDOUSLY INFORMATIVE AND THAT WILL INFORM CLINICAL STUDIES BECAUSE IT GIVES BIOMARKERS WE DON'T HAVE RIGHT NOW. >> THANK YOU. >> JOHN YOU CAN HAVE THE LAST BRIEF QUESTION THEN MOVE ON. >> WE'RE SO LUCKY TO WIND UP IN THE RIGHT HAND CORNER BOX WITH YOUR EXAMPLE WHICH IS GOOD, WE'RE NOT HOME FREE WITH PARKINSON'S OR ALZHEIMER'S DISEASE. I WONDER IF WE HAVE GONE BEYOND THE POINT MONOTHERAPY IS CONCEIVABLE TO WORK IN THESE HETEROGENEOUS DISEASES WHICH IS A LOT OF COMORBIDITIES SO ALZHEIMER'S PATIENTS, 50% HAVE LOUIS BODIES, AND AFTER AGE 50 THE NUMBER OF CEREBRAL VASCULAR DISEASE GOES UP TO -- FROM 50% TO 75%. THE A BETA CASCADE DOES NOT EXPLAIN HOW A BETA CHRIST THE PATHOLOGIES SO DO WE NOT HAVE TO THINK ABOUT CLINICAL TRIALS IS THAT USE COMBINATION THERAPY? I FEAR THE NEXT CLINICAL TRIAL DONE ALL THE BIOMARKERS MOVE IN ALL THE RIGHT DIRECTION BUS THE DISEASE WILL PROGRESS BECAUSE THEY HAVE TAU ON BOARD, EVEN FAD THERE'S LOUIS BODY. >> THAT'S WHY YOU HAVE TO GO TO MUTATION SPECIFIC TRIALS THAT'S WHY. BELIEVE ME, I THINK IF YOU START -- NOT COMBINATION ISN'T EVENTUALLY GOING TO BE THE ANSWER FOR INDIVIDUAL PATIENTS, I THINK GOING INTO COMBINATION THERAPY STRAIGHT AWAY JUST GOING TO AN ENORMOUS STATISTICAL BLACK HOLE. I REALLY THINK IT'S JUST -- >> YOU FAIL TO SEE A CLINICAL SIGNAL BECAUSE YOU CONVERT ALZHEIMER PATIENTS TO TAUOPATHY PATIENTS. >> THAT'S WHY YOU GO TO MUTATION SPECIFIC INDIVIDUALS. >> BELIEVE ME IN FAD THERE'S SINUKLINE PATHOLOGY. >> YOU DON'T KNOW WHERE THE PROBLEM STARTS THEN. IF YOU READ THE AMYLOID HYPOTHESIS YOU'LL UNDERSTAND IT BETTER. IT WAS WRITTEN BEFORE SINUKLINE WAS KNOWN, JOHN, YOU KNOW THAT. >> SURE. >> TAKE INTO ACCOUNT CEREBRAL VASCULAR DISEASE AS WELL. I'M SORRY. >> SO JUST ONE POINT -- >> FORGETTING WHERE WE HAVE GONE TO SEE 100 YEARS AGO. >> I'M GOING TO INTERJECT WITH THESE TWO JOHNS AND WRAP UP. >> WE'RE GOOD FRIENDS. >> ONE THING WE DIDN'T DISCUSS IS LOWER DOWN ON THE LIST OF PRIORITIES WAS GETTING A BETTER UNDERSTANDING OF COMORBIDITIES ACROSS NEURODEGENERATIVE DISEASE WHETHER IT BE DIFFERENT PROTEINS REPRESENTED IN A SICKLE DISEASE. SO THAT'S SOMETHING WE THOUGHT WAS IMPORTANT. WITH THAT I THINK WE NEED TO DRAW THIS PANEL DISCUSSION TO A CLOSE. TOM, WILL YOU TAKE IT TO THE NEXT SESSION? [APPLAUSE] >> I SHOULD THANK MY PANELIST AS WELL. >> WE WILL DO THIS NEXT ONE VIA TELECONFERENCE. AM I MOVING THE SLIDE OR SOMEONE ELSE GOING TO MOVE THE SLIDE? OKAY. DMITRI KRAINC, CAN YOU HEAR ME LOUD AND CLEAR? >> I CAN HEAR YOU. >> LOOKING FORWARD TO YOUR PRESENTATION ON TARGET IDENTIFICATION AND VALIDATION. THANKS, DMITRI. >> THANK YOU, JOHN. GOOD AFTERNOON, EVERYBODY. FIRST I WOULD LIKE TO THANK NINDS FOR ORGANIZING THIS VERY IMPORTANT VERY INFORMATIVE WORKSHOP AND I'M REALLY SORRY I COULDN'T MAKE IT IN PERSON. ALL FLIGHTS FROM CHICAGO TO D.C . WERE CANCELED QUEUE TO WEATHER. THIS MORNING THE WEATHER CHANNEL IN CHICAGO SAID THAT ANYONE VENTURING OUTSIDE WITHOUT WRAPPING UP CAN FREEZE IN A MATTER OF SECONDS. WHICH I FOUND VERY INTERESTING. ANY WAY, I DID MAKE IT TO WORK. PLEASURE TO BE HERE, THANK YOU SO MUCH. THE MAIN TOPIC OF MY PRESENTATION IS TARGET ENGAGEMENT IN PARKINSON'S DISEASE, THIS IS DISCUSSED THIS MORNING ESPECIALLY JOHN DUNLOP WHO HAS DONE A GREAT JOB INTRODUCING THE THE TOPIC. ONE PRACTICAL QUESTION THAT COMES UP OFTEN INCLUDING IN REVIEWS IS TO DEFINE FEATURES OR ATTRIBUTES OF TARGETS THAT JUSTIFY THEIR ADVANCEMENT INTO TRANSLATIONAL STUDIES. NEXT SLIDE, PLEASE. LET ME -- THIS IS THE FIRST -- OUR FIRST RECOMMENDATION IS TO DEFINE THESE FEATURES AND I WOULD LIKE TO DO THIS BY COUPLE OF EXAMPLES, LET ME START WITH NUMBER 2, ON THE BOTTOM, IS THAT REPRESENTS A MORE COMMON SITUATION IN OUR TRANSLATIONAL EFFORTS UP TO DATE. WE HAVE SEEN EXAMPLES OF AGENTS, ANTIOXIDANTS OR COQ AGENTS THAT HAVE PARTIAL CORRECTION, PARTIALLY CORRECT PATHOGENIC ABNORMALITIES THAT WE SEE IN CELL MODELS OR ANIMAL MODELS OF DISEASE, SOMETIMES THEY PROLONG SURVIVAL, SOMETIMES THEY RESCUE PATHOLOGY. THAT IS SUFFICIENT TO MOVE AGENTS TO CLINICAL TRIALS. ONE PROBLEM WITH THIS APPROACH HAS BEEN THAT WE HAVEN'T HAD GOOD WAY TO ASSESS IT CAN BE MONITORED IN PATIENTS. THIS WAS WHAT JOHN WAS DESCRIBING WELL IN HIS TALK. INSTEAD WE HAVE TO RESORT TO MORE EXPEPSIVE CLINICAL TRIALS TO FIND OUR THESE COMPOUND WORK. ANOTHER EXAMPLE THAT WILL BE MORE ALMOST AN IDEAL SITUATION IS NUMBER ONE, BASED ON WHAT (INAUDIBLE) IN TERMS OF GENETIC SPECIFIC PATIENT POPULATION. SO WE HAVE SPECIFIC TARGET ENZYME X, COULD BE GBA, THAT HAS BEEN MENTIONED TODAY A COUPLE OF TIMES IT SHOWS THE DIRECT MECHANISTIC RELATIONSHIP THROUGH ALPHA SYNUCLEIN. SO WHEN THE ENZYME IS ACT KATE INVESTIGATED ALPHA SYNUCLEIN GOES DOWN AND WHEN THE ENZYME IS MUTATED AND HYPOACTIVE ALPHA SYNUCLEIN WILL ACCUMULATE. SO THE NEXT STEP WILL BE TO IDENTIFY THERAPEUTIC AGENT THAT ACTIVATES THE ENSIEM >> EXAMPLE NUMBER 2 IS HERE IT SHOULD BE POSSIBLE TO MEASURE ENZYME ACTIVITY EITHER CSF, BLOOD SAMPLES OR MAYBE OTHER PERIPHERAL COMPARTMENTS. SO YOU WOULD BE ABLE TO SHOW THIS TARGET IS ENGAGED SMALL MOLECULE ENZYME ACTIVATED AND NEXT QUESTION, REQUEST IF IT'S ACTIVATED IS THIS ENZYME LOWERING ALPHA SYNUCLEIN IN THIS PATIENTS. THIS CAN BE MEASURED IN PERIPHERAL COMPARTMENTS OR LIGANDS IN THE BRAIN. SO THIS ILLUSTRATES A CASE OF TARGETED THERAPY OR AS SOME CALL IT RESCISSION OR PERSONALIZED THERAPY, PATIENTS WHO HAVE DECREASE ACTIVITY OF THIS ENZYME, (INDISCERNIBLE) GBA-1. YOU HAVE THE MUTATION OR SOME CASES PATIENTS DON'T HAVE MUTATIONS IN PARTICULAR TARGETS. BUT THEY STILL HAVE LOWER ACTIVITY. YOU WILL GET SPECIFIC THERAPY AGAINST THE ENZYME AND MONITOR THE ACTIVITY OF THIS ENZYME OR TARGET IN VIVO BEFORE YOU GO INTO MORE EXPENSIVE TRIALS. NEXT SLIDE, THIS HAS BEEN SUCCESSFULLY ACCOMPLISHED IN ONCOLOGY, I DON'T WANT TO GO INTO ANY GREAT DETAILS BUT TARGETED THERAPY IS QUITE SUCCESSFUL IN ECOLOGY NOT JUST DIRECTING CHOICE AND DOE ADVANTAGE EARLY DETECTION AND CATEGORIZATION OF DISEASE THERE'S BREAK THROUGHS IN TARGETED THERAPIES MELANOMA AND SOME FORMS OF LUNG CANCER, I HOPE ANTICIPATED WITH RECENT ADVANCEMENT IN GENETIC AND PARKINSON'S DISEASE WE SHOULD BE ABLE TO DEVELOP SIMILAR TARGETED THERAPIES FOR PARKINSON'S DISEASE, THAT GOES TO SOME OF THE ISSUES DISCUSSED IN THE PANEL A FEW MINUTES AGO. PLEASE GO TO SLIDE NUMBER 3. OUR NEXT RECOMMENDATION WAS TO DEVELOP ALPHA SYNUCLEIN IMAGING AGENTS TO MEASURE BURDEN IN ANIMAL MODEL AND IN PATIENTS. THE EFFORT TO DEVELOP AGENTS HAVE BEEN ONGOING IN INDUSTRY AS WELL AS MICHAEL J. FOX. IT GOES WITHOUT SAYING THAT HAVING A RELIABLE AND NON-INVASIVE ALPHA SYNUCLEIN IN CNS WOULD GO A LONG WAY IN TRANSLATIONAL EFFORTS. WE CAN TRACK ALPHA SYNUCLEIN IN RELATION TO DISEASE PROGRESSION IN RESPONSE TO THERAPY. WE CAN ALSO STUDY CORRELATION OF ALPHA SYNUCLEIN LEVELS IN THE BRAIN WITH LEVELS IN CSF OR BLOOD OR OTHER PERIPHERAL TISSUES. AND OF COURSE ONE OF THE CAVEATS OF THIS APPROACH I THINK THAT WAS MENTIONED BRIEFLY BEFORE IS THAT IT MAYBE DIFFICULT TO ASSESS TOTAL BURDEN OF VARIOUS ALPHA SYNUCLEIN SPECIES, MONOMERS AGGREGATE MODIFY POST TRANSLATIONALLY MODIFIED. ONE IS ENVISION THE SITUATION WHERE WE HAVE A LARGE ALPHA SYNUCLEIN AGGREGATE THAT DIMY NICHE THE NUMBER BUT MAYBE DUE TO THIS AGGREGATION THAT LEADS TO INCREASED BURDEN OF TOXIC OLIGOMERS NOT DETECTED BY THESE METHODS. SO TECHNICAL ISSUES HAVE TO BE ADDRESSED BUT NEVERTHELESS IT WILL PLAY ANOTHER ROLE IN OUR EFFORTS IN PARKINSON'S DISEASE. NEXT SLIDE PLACE. SO THE NEXT RECOMMENDATION IS TO DEVELOP INTERMEDIATE MARKERS OF DRUG EFFICACY IN EARLY TRANSLATIONAL STUDIES IN ORDER TO SUPPORT MORE COST EFFECTIVE SMALLER PROOF OF CONCEPT STUDIES. LET ME ILLUSTRATE WITH THE FOLLOWING EXAMPLE WE FOUND A COMPOUND THAT ACTIVATES ENZYME X DISCUSSED A MINUTE AGO. AND THE COMPOUND IS ACTIVATING THOSE ENZYME IN CSF OR BLOOD SAMPLES AND WE MAY FIND BY PET LIGAND ALPHA SYNUCLEIN LOWERS ALPHA SYNUCLEIN IN THE BRAIN AS WELL. WHAT DO WE MEASURE NEXT TO CONVINCE OURSELVES THAT THE STUDY SHOULD BE INVESTED IN THE NEXT STAGE. OUR PANEL HAS SUGGESTED SEVERAL POSSIBILITIES, THAT'S -- THIS IS A PARTIAL LIST NEUROIMAGING BIOMARKERS, DOPAMINE TRANSPORTER, BOLE MRI, CONNECTIVITY MAPS AND SO FORTH. NEUROPHYSIOLOGICAL MARKERS PROEM CHROMICS APPROACHES MEASURED BY ALPHA SIGH NEW KLINE USED IN LABELING FOR EXAMPLE, THAT'S INTERESTING AS WELL, COULD WE MEASURE TURN OVER OF ALPHA SYNUCLEIN IN VIVO. THE UTILITY OF THESE APPROACHES WILL DEPEND ON SENSITIVITY AND RATE OF CHANGE IN VARIOUS STAGES OF DISEASE, THAT REMAINS TO BE SEEN BUT NEVERTHELESS THERE IS A CLEAR RECOGNITION THESE KINDS OF INTERMEDIATE MARKERS WOULD POTENTIALLY HELP US LOWER THE COST OF TRANSLATIONAL STUDIES. LET ME JUST SUMMARIZE THE LAST SLIDE, THIS IS THE SUMMARY OF OUR THREE RECOMMENDATIONS. THE NEXT SLIDE, PLEASE. THE STAGE OF THE PROCESS IS ABSOLUTELY CRITICAL, IN TERMS OF FINDING NEW TARGETS AND PATHWAYS THAT WILL BE AMENABLE TO DEVELOP PERSONALIZED TREATMENTS FOR OUR PATIENTS. THIS IS SORT OF THE THEME THAT HAS BEEN DISCUSSED ALL DAY HOW TO PRIORITIZE FUNDING IN TERMS OF INPUT STAGE OPPOSED TO LATER STAGE TRANSLATIONAL DEVELOPMENT. TO TO PARAPHRASE LOW INPUT HIGH THROUGH PUT NO OUTPUT, THAT DESCRIBES SOME OF THE PROBLEMS THAT WE HAVE HAD IN OUR PAST EFFORTS. BUT VERY OPTIMISTIC WE'RE ON THE RIGHT TRACK. EVIDENCE BY THIS WORKSHOP DISCUSSION IS IMPORTANT AND INFORMATIVE AND WITH THAT I'LL CLOSE AND OPEN FOR QUESTIONS. THANK YOU SO MUCH. >> HAVE THE PANELISTS COME UP. >> I WANT TO ENCOURAGE THE AUDIENCE YOU'LL HAVE PRIORITY. SO ANYBODY WHO HAS A QUESTION, PLEASE COME UP. MAYBE YOU CAN START AS WE DID THE LAST TIME AND HAVE PANELISTS HIGHLIGHT FOR US WHAT THINK THINK ARE THE MOST IMPORTANT POINT OR POINTS IN THIS AREA. (OFF MIC) >> AMYLOID IMAGING REVOLUTIONIZED ALZHEIMER'S DISEASE. IT'S COMPLETELY REVOLUTIONIZED THE WAY PEOPLE THINK ABOUT THE DISEASE. AND IT'S CLEAR SYNUCLEIN IMAGING IS EQUALLY IMPORTANT, THOUGH I WOULD REMIND PEOPLE THAT SIGH NEW KLINE IS NOT QUITE DEFINITIVE MARKER FOR PARKINSON'S DISEASE AMYLOID AS ALZHEIMER'S DISEASE BECAUSE SOME MUTATION CARRIERS WHO HAVE PERFECTLY GOOD CLINICAL PARKINSON'S DISEASE HAVE NO LOUIS BODY PATHOLOGY SO IT'S NOT AS CLEAR CUT. CLEARLY IMPORTANT. I AGREE MECHANISM HAS TO BE THE WAY WE GO. WHAT WE'RE REALIZING IN ALZHEIMER'S DISEASE, VERY IMPORTANT FOR TARGET ENGAGEMENT, TAKING CSF AS A ROUTINE IS SOMETHING THAT HAS TO BE CONSIDERED. AND WE NOW HOW IT USED TO BE 20 YEARS AGO WHEN ALMOST EVERY PATIENT HAS CSF TAKEN. THAT'S SOMETHING I KNOW THERE ARE INITIATIVES HERE IN THE U.S. ABOUT AND THAT NEEDS TO BE PUSHED VERY HARD I THINK, WE'RE GOING TO DO TARGET ENGAGEMENT CSF IS GOING TO BE IMMENSELY VALUABLE. >> SO ON THAT TOPIC, BECAUSE DMITRI BUT TALKING ABOUT ENGAGEMENT AND JOHN DUNLOP TALKED ABOUT THAT, I WAS THINKING IN MY HEAD, INDUCING AUTOPHAGY, RAPAMYCIN, IS A NATURAL PRODUCT HOW COULD ONE ASSESS RAPAMYCIN TARGET ENGAGEMENT IN HUMAN BRAIN? BECAUSE IT'S A CYTOSOL, IT WON'T BE IN CSF. TO STRETCH THAT POINT, TO CHALLENGE JOHN, NATURAL PRODUCTS, A LOT EVOLVE TO SOLVE PHARMACODYNAMIC PROBLEMS. AND TO GET ACROSS THE BLOOD BRAIN BARRIER THAT, MIGHT BE A SUBCLASS OF COMPOUNDS ONE MIGHT NOT NEED TO BE SO STRINGENT AS YOU MENTIONED. YOUR THOUGHTS ON THAT. MAYBE AN EXAMPLE I WOULD GIVE FOR TARGETS NOT SO EASY TO DO, PHOSPHODIEST RACE HEAVILY PURSUED TARGETS INITIALLY IN PSYCHIATRY AND NOW PD 10 HUNTINGTON IS PURSUEDED BY NUMBER OF GROUPS. NUMBER OF GOOD WELL BEHAVED SIGNAL TO NOISE IMAGING AGENTS FOR CELLULAR PHOSPHODIEST RACE. MORE CHALLENGING THAN CELL SURFACE GPCR BUT WE SHOULD BE ENCOURAGED BY THE SUCCESS WITH THE PDs, RAPAMYCIN IS CLEARLY, I DON'T THINK ANYBODY TRY TO DEMONSTRATE AUTOPHAGY BY RAPAMYCIN IN HUMANS AND IMMUNOSUPPRESSIVE EFFECTS WHICH YOU CAN DEMONSTRATE ROBUSTLY IN A HUMAN PERSON IF YOU DO SO. >> CAN I COMMENT SOMETHING ON P WHAT RICHARD BROUGHT UP? RICHARD, I THINK IT'S AN INTERESTING QUESTION WITH RAPAMYCIN, ONE OF THE PROBLEMS AS YOU KNOW IS THAT RAPAMYCIN EFFECTS SO MANY DIFFERENT PATHWAYS AND IN TERMS OF ENGAGING A SPECIFIC TARGET IT'S A REAL CHALLENGE. WHAT IS THE TARGET? IT AFFECTS TRANSLATION AS WELL AND PATHWAYS. THAT'S BEEN PART OF THE PROBLEM WITH OTHER AGENTS THAT WE HAVE HAD, HITTING TOO MANY THINGS AND WE HAVEN'T BEEN ABLE TO NARROW DOWN TO SOMETHING MORE SPECIFIC YOU CAN ARGUE MANY DRUGS WE CAN TAKE WE DON'T KNOW THE LEVEL OF DETAIL IN TERMS OF MECHANISM, WE TAKE DRUGS THAT HIT PATHWAYS AND THEY STILL WORK. THAT IS REALLY THE -- I THINK THE BROADER QUESTION, DO WE HAVE TO REQUIRE THAT LEVEL OF DETAIL FOR EVERY DRUG WE'RE TRYING TO DEVELOP. OBVIOUSLY WE HAVE BEEN SUCCESSFUL BY NOT DOING IT SO THE REACTION IS WE SHOULD BE DOING IT FROM NOW ON BUT REALITY, IT'S A REAL INTERESTING DISCUSSION I THINK. >> TODD, DID YOU HAVE A QUESTION? >> FROM THE FOX FOUNDATION. MY QUESTION IS LESS ABOUT THE SPECIFIC SCIENCE AND MAYBE MORE COMMUNICATION ISSUE BECAUSE I HAVE DONE THIS MYSELF LOOKING AT ALL THE TARGETS THAT ARE PROPOSED IN PARKINSON'S AND ALL THE MISSING PIECE OF INFORMATION THAT WE HAVE AGAINST THEM. AND HOW CAN WE ENCOURAGE THIS BETTER BACK AND FORTH FLOW BETWEEN WHAT THE INDUSTRY WANTS TO SEE TO SOLVE ON THE TARGET AND THE CAPABILITIES OF THE TALENTED ACADEMICS IN THIS AREA. THERE'S NOT A LACK OF EFFORT, MAYBE THE EFFORT IS MISDIRECTED. >> I THINK MAYBE THE POINT I WAS TRYING TO MAKE TODD IS THAT IT'S MAYBE NOT MISDIRECTED BUT WHETHER IT'S BEEN INTEGRATED ACROSS THE BASIC TRANSLATIONAL AND CLINICAL WHERE I THINK YOU TEND TO FIND MAYBE MORE ACADEMIC SIDE FOLKS MORE FOCUSED ON BASIC SCIENCE WITHOUT THINKING WHAT WOULD IT TAKE TO GET MARKERS THAT SUPPORT ADVANCEMENT WHEREAS IF WE TACKLE THAT SAME QUESTION WITHIN A DRUG DISCOVERY PROJECT, WE THINK VERY MUCH ACROSS THE SPECTRUM AND INTEGRATED MANNER AND YOU HAVE PEOPLE WORKING ON TOOLS AN REAGENTS. THAT ARE NOT THE HIGH POTENCY MOLECULE INTENDED TO MODULATE THE TARGET BUT OTHER TOOLS AND REAGENTS TO HELP DEFINE THE BIOMARKERS AND SUPPORT ADVANCEMENT SO I WOULD LIKE TO THINK HOW WE CAN INTEGRATE SOME OF THOSE EFFORTS THAT ARE IN SOME OF THE ACADEMIC TRANSLATIONAL CENSUS PERHAPS. >> FOR EXAMPLE, GETTING SOME OF THOSE TOOL MOLECULES BETTER DISTRIBUTED SO THE ACADEMICS UTILIZE BETTER CHARACTERIZED TOOLS TO VALIDATE AND TEST HYPOTHESES. THAT'S ONE SUGGESTION TO TRY TO TAKE ON. >> (INAUDIBLE) PHARMACEUTICALS. BRING TOGETHER THINGS THAT SHOWED UP IN THE LAST PRESENTATION AND JOHN POINTED OUT THE VALLEY OF DEATH AND THE VALLEY OF DEATH IS NOT A BAD NAME. THE VALLEY OF DEATH IS A GOOD THING, WE SHOULD BUILD A BEAUTIFUL CEMETERY IN THE VALLEY OF DEATH. HAD BEEN YOU LOOK AT THE SUCCESS RATE OF THINGS IN PHASE 1 AS JOHN POINTED OUT, 7% IF WE DID A FABULOUS JOB ALL THIS WORK THAT EVERYBODY IS DOING HAD A HUGE IMPACT IT MIGHT GO UP TO 15% WHICH MEANS 85% WOULD DIE OF TRANSLATIONAL DEVELOPMENT AND IN THE PIPELINE, I APPRECIATE THE ANALOGY THERE BUT THE PIPELINE IS ACTUALLY A -- WE GET RID OF THINGS THAT ARE NOT GOING TO WORK AND KEEP THE THINGS THAT DO. TARGET ENGAGEMENT ISSUES ARE REALLY IMPORTANT BECAUSE THEY CHANGE EFFICACY OF SUCCESS. WHAT WE DO ALL THE TIME IS GET TO THE POINT OF CLINICALLY TEST THE HYPOTHESIS GENERATED BY BASIC RESEARCH SO WHEN YOU HAVE THE TARGET ENGAGEMENT WHEN YOU KNOW YOU ENGAGE THE TARGET YOU GO INTO THE CLINIC, MOST OF THE TIME IT'S GOING TO FAIL BECAUSE WE'RE NOT THERE. WE CAN WALK AWAY WE CAN TAKE THE MECHANISM OUT OF THE PIPELINE AND TEST THE NEXT THING. ALTHOUGH IT WAS NEVER GREAT. IF YOU CAN FAIL CLEANLY AND CHEEPLY THEN THEY DO THE NEXT THING. THAT WILL IMPROVE THE RATE WHICH WE HAVE EFFECTIVE THERAPIES. SO I THINK THAT'S THE KIND OF THING WE OUGHT TO BE DOING. FAILING FAST AND FAILING CHEAP AND THEN GETTING ON WITH NEXT THING. CERTAINLY WOULD AGREE WITH PHIL THAT YOU CAN SUCCEED CHIEFLY. I HAD A QUESTION FOR THE TWO JOHNS. I THINK THIS MORNING YOU LISTEN TO THE CLINICAL TALKS AND REALLY THE HEAVY FOCUS ON QUALITY OF LIFE FOR PARKINSON'S PATIENTS AND CLINICAL OUTCOME MEASURES, AND JOHN YOU HINTED AT THIS THAT ALPHA SYNUCLEIN MAY NOT IN SOME CASES BE COMPLETELY RELIABLE BIOMARKER BUT JOHN YOU MENTIONED MOVING FROM ANIMAL BEHAVIOR EXPERIMENTS TO MORE HISTOLOGICAL END POINTS. I WONDER MY SENSE IS THOUGH WE WANT DISEASE MODIFYING AGENTS PHARMA IS MORE OPEN NOW TO SYMPTOMATIC THERAPIES AND HAVING A SUCCESSFUL CLINICAL TRIAL AND SORT OF IN THAT CONTEXT HOW YOU THINK ABOUT BIOMARKERS. WHAT SHOULD WE BE GOING AFTER. I THINK THE QUESTION GOT RAISED IN A POINTED WAY THIS MORNING, IF YOU HAVE A POSITIVE BIOMARKER BUT NO CLINICAL RESULT OR CLINICAL RESULT AND NO BIOMARKER RESULT HOW YOU USE THOSE IN THE WHOLE PROCESS OF MAKING DECISIONS. >> FIRST BEHAVIORAL THINGS, THE GAMMA SECRETASE INHIBITORS IN MICE IMPROVED BEHAVIORS AND IN MAN MADE BEHAVIOR WORSE. SO TO ME THAT TELLS YOU CERTAINLY WITH REGARD TO THAT MECHANISM THAT BEHAVIOR IS NOT A USEFUL BIOMARKER. I HAVE ALWAYS FAVORED HISTOLOGICAL END POINTS MYSELF. I DIDN'T -- NOW, IS THAT AN ANSWER TO HALF YOUR QUESTION, ISN'T IT? WHAT WAS THE OTHER HALF? >> TRYING TO -- WHAT IS -- IF WE'RE TRYING TO FOCUS ON QUALITY OF LIVING ULTIMATELY IN PARKINSON'S PATIENTS, WHAT SHOULD WE BE FOCUSING ON AS BIOMARKERS, AND WHAT DO WE DO IN LIGHT OF POSITIVE OR NEGATIVE RESULT IN SOME CASES BECAUSE I THINK THE QUESTION CAME UP THIS MORNING, WE HAVE TO VALIDATE THESE MARKERS IN SOME WAY WITHOUT VALIDATED BIOMARKERS THE KEY THING REALLY IS TO MAKE SURE YOUR MOLECULES ACTING, WHAT JOHN MENTIONED EXPRESSION OF PHARMACOLOGY, AT LEAST COMBINING THE TARGET IN DOING WHAT IT'S SUPPOSED TO DO, UNTIL WE HAVE THOSE BIOMARKERS VALIDATED. I'M INTERESTED IN YOUR THOUGHTS. >> YOUR INTEREST IS ILL FOUNDED. [LAUGHTER] >> I CAN'T GIVE AN ANSWER TO THAT BUT IF A BIOMARKER DOES NOT PREDICT CLINICAL OUTCOME IT'S USELESS, IT'S REALLY -- YOU HAVE TO BE DROPPED. BUT YOU NEED SPECIFIC EXAMPLES, I THINK WE ONLY NOW WITH THESE LAST TRIALS BEGINNING TO UNDERSTAND WHAT CSF TAU IS AS A BIOMARKER IN TERMS OF AMYLOID TREATMENT, ONLY BEGINNING TO UNDERSTAND THAT NOW AND THE IDEA REFLECTED TAU PATHOLOGY LOOKS SIMPLY WRONG. SO BIOMARKERS ARE SUBJECT TO ALL SORTS OF CAVEATS WHICH AREN'T ALL OBVIOUS. WE WANT TO OBVIOUSLY IMPROVE QUALITY OF LIFE AND IF BIOMARKERS DON'T PREDICT THAT, IT'S NOT USEFUL. >> CAN I COMMENT BEFORE WE TAKE THE QUESTION FROM THE FLOOR? I DID MAKE THE POINT ABOUT SWITCHING FROM BEHAVIORAL TO MORE PHYSIOLOGICAL AND HISTOLOGICAL END POINTS, I DIDN'T MEAN TO SAY THERE WOULD BE NO UTILITY OF BEHAVIORAL END POINTS BUT THERE'S A LOT WHERE WE SORT OF INVALIDATED UTILITY, THINKKING SPECIFICALLY A LOT OF COMPOUNDS THAT HAVE SHOWN PUNITIVE COGNITIVE ENHANCING ACTIVITY AND PRE-CLINICAL RODENT MODELS AND SUBSEQUENTLY GONE INTO TRIALS AND AD PATIENTS FOR EXAMPLE AND FAILED TO SHOW COGNITIVE BENCH I THINK WE CAN SHOW SOME DEFINITIVELY THERE'S SOME MODELS THAT ARE NOT HELPING WITH RESPECT TO TRANSLATION. IT'S MORE ABOUT WEEDING OUT ONES NOT INFORMATIVE AND FOCUSING ON ONES THAT MIGHT BE BE >> LAST QUESTION. >> IT'S A COMMENT AND KIND OF A WARNING TOO, IN A STROKE WE HAVE LEARNED THAT IF CLINICAL TRIAL IS BASED JUST IN HISTOLOGY IS NOT GOOD ENOUGH I THINK WE NEED TO REMEMBER WE NEED TO LOOK FROM ALL THE DIFFERENT ANGLES, THE DIFFERENT BIOMARKERS, AS POLITICAL SCIENTIST WHEN I FIND IMPROVEMENT IN HISTOLOGY AND NO IMPROVEMENT IN BEHAVIOR, THERE'S SOMETHING WRONG. USUALLY MY DATA CORRELATES AND I THINK WE NEED TO KEEP THAT IN MIND. >> THANK YOU, PANELISTS. >> INTRODUCE THE NEXT SESSION. DR. MICHAEL LEE. AND CLIVE SVENDSEN ARE TALKING MODELING PD PATHWAYS FORWARD AND REVERSE TRANSLATION. >> DO I JUST MOVE THIS HERE? GREAT. SO THIS SESSION IS A NICE SEGUE FROM WHAT WE HAVE BEEN DISCUSSING, ALSO THE -- WHAT WE HAVE DISCUSSED THIS MORNING FROM THE CLINICAL GROUP SO WE HAVE -- ESPECIALLY MY TOPIC WILL HAVE RELEVANCE TO TRY TO DEVELOP POTENTIAL THERAPIES FOR NON-MOTOR FEATURES OF PARKINSON'S DISEASE SO THESE TWO POINTS THAT CLIVE AND I WILL DISCUSS IS FIRST IS THE WHAT CAN WE DO WITH EXISTING MODELS NOW TO FACILITATE DEVELOPMENT OF THERAPEUTICS? DISEASE MODIFYING THERAPEUTIC. AND CLIVE WILL DISCUSS WHAT CAN BE DONE IN THE FUTURE POTENTIALLY IDENTIFY TARGETS AND DEVELOP THERAPEUTIC. SO IN MODELING PD THE RECOMMENDATION WAS THAT PRE-CLINICAL STUDIES TARGETING ALPHA SYNUCLEIN PATHOLOGY WE SHOULD IDENTIFY SETS OF ANIMAL MODELS THAT ARE STANDARDIZED WITH SOME CONSENSUS GUIDELINES. I THINK THERE IS A SUFFICIENT NUMBER OF MODELS WHERE SIGNIFICANT OUTCOME MEASURES RELEVANT TO DISEASE COULD BE EVALUATED. AND BASICALLY THE APPROACHES ARE TO IDENTIFY A FEW MODELS THAT ARE PREDICTIVE AND IF NOT STANDARD MODELS ARE USED TO FIND THE OUTCOME MEASURES FOR TARGETING ALPHA SYNUCLEIN. AND ALSO TRYING TO DETERMINE WHETHER ON ALL THESE DIFFERENT MODELS WHETHER SPECIFIC ABNORMALITIES ARE A COMMON FEATURE IN VARIETY OF DIFFERENT ALPHA SYNUCLEIN BASED MODELS. ALSO TO PROVIDE A BACKING OF STANDARDIZED COLLECTION OF TISSUES AND SAMPLES FROM THE ANIMALS SO THAT THE GENERAL SCIENTIFIC COMMUNITY CAN ANALYZE THEM AND WE PROPOSE TO DO THIS BY ORGANIZING POTENTIALLY NINDS SPONSORED WORKSHOP OR PANEL AND COME UP WITH SOME CONSENSUS GUIDELINES. SO WHY WOULD WE FOCUS ON ALPHA SYNUCLEIN PATHOLOGY? PART OF THIS COMES FROM GENETIC EVIDENCE WHERE MOST OF YOU KNOW, MOST PARKINSON'S DISEASE HAVE NO KNOWN COGNITIVE, IT'S SPORADIC BUT SMALL PORTION CAUSED BY GENETIC MYCATION. THERE'S TWO BROAD TYPES OF FAMILIAL FORMS OF PD. ONE IS AUTOSOMAL DOMINANT, THE OTHER IS RECESSIVE. OBVIOUSLY ALPHA SYNUCLEIN MUTATIONS IN PARKINSON'S TO BE CAUSED BY MUTATIONS IN BOTH ALLELE. IF YOU LOOK AT THE CLINICAL FEATURES IN THE NEURAL PATHOLOGICAL FEATURES OF DISEASES, WHAT YOU FIND IS THE AUTOSOMAL DOMINANT FORM, THE ALPHA SYNUCLEIN FAMILIAL PD CAUSED BY MUTATION SEEMS TO PHENOCOPY WHAT YOU SEE MAJORITY OF SPORE ACTIVITIES. IN OTHER WORDS, IT IS PROGRESSIVE WITH SIGNIFICANT NON-MOTOR FEATURES ALPHA SYNUCLEIN ABNORMALITIES. SO OUR PERSPECTIVE WAS THAT REGARDLESS OF DETAILS ALPHA CITY KNEW CLIENT ABNORMALITY WAS SOMEHOW A PRIMARY DRIVER OF SOME OF THESE PROGRESSIVE NON-(INAUDIBLE) FEATURES OF PARKINSON'S DISEASE. WHY IS THAT IMPORTANT? OBVIOUSLY THIS WAS IN DETAIL THIS MORNING BY THE CLINICAL GROUP BUT WE KNOW THAT WITH PARKINSON'S DISEASE IS NOT JUST LOSS OF DOPAMINERGIC NEURONS, A HOST OF NEURONS ARE AFFECTED. WHAT WE BELIEVE IS THAT THIS ALPHA SYNUCLEIN MUTATION IS PICTURED LOUIS BODY OCCURRING IS RESPONSIBLE FOR THIS. DON'T GET ME WRONG. I THINK THE MODELING -- BEING ABLE TO MODEL DOPAMINERGIC NEURONS PARTICULARLY USING TOXINS HAVE ENORMOUS BENEFIT FOR DEVELOPMENT OF SYMPTOMATIC THERAPIES. AND THERAPYINGS ARE OUTSTANDING BUT UNFORTUNATELY WE HAVE HAD EFFECTIVE THERAPIES FOR NON--- FEATURES. WE'RE HOPING THAT THAT WILL LEAD TO BETTER NEUROPROTECTIVE OR DISEASE MODIFICATION THERAPIES. SO JUST TO GO OVER WHAT HAS BEEN SUCCESSFUL IN THESE MODELS IN TERMS OF NEURAL PROTECTION TRIAL IN PRE-CLINICAL TRIALS, HAVE NOT SHOWN BENEFIT IN HUMAN TRIAL ARE SOME OF THE COMPOUNDS LISTED HERE. IS THAT TO SAY THERE WAS SOMETHING WRONG WITH THE TOXIN MODEL PER SE, THE REASON WHY IT DIDN'T WORK COULD BE A LOT OF THINGS, OBVIOUSLY THERE'S COMPLICATIONS, BUT GIVEN THE FACT A LOT OF NON-MOTOR SYMPTOMS OF PD IS POTENTIALLY MODELD SELECTIVELY CAUSE NEURODEGENERATION OF DOPAMINERGIC NEURON MAY NOT BE FULLY APPROPRIATE. ALPHA SYNUCLEIN MODEL AT LEAST SOME OF THE INITIAL STUDIES ARE BEHAVING -- THEY RESPOND DIFFERENTLY TO THERAPIES, OR PRE-CLINICAL THERAPIES THAT PROTECT NEURODEGENERATION TOXIN MODEL SO THERE WAS A PROJECT CALLED THE SYNAPSE PROJECT ATTEMPT TO STANDARDIZE PRE-CLINICAL THERAPEUTIC RECOMMEND MEN IN ANIMAL MODELS. IN THIS STUDY THEY TRY (INAUDIBLE) THIS WAS DONE IN CONJUNCTION WITH NINDS AND ALSO RESEARCH TRIANGLE INSTITUTE IN NORTH CAROLINA. BOTH COMPOUNDS WERE ABLE TO ATTENUATE NEURODEGENERATION IN A TOXIN MODEL. UNFORTUNATELY NEITHER COMPOUND WORKED IN THE ALPHA SYNUCLEIN TRANSGENIC ANIMALS. BUT THE THING IS, IT'S NOT BECAUSE YOU CAN NOT HAVE A PRE-CLINICAL EFFICACY OR EFFECT ALPHA SYNUCLEIN TRANSGENIC MODEL BECAUSE OTHER COMPOUNDS HAVE SHOWN PRE-CLINICAL EFFICACY IN THE ALPHA SYNUCLEIN TRANSGENIC MODEL SO WE BELIEVE POTENTIALLY TIME WILL TELL BUT THAT TOXIN BASED MODEL IS NOT SHOWN TO BE PREDICTIVE FOR FUTURE TRIALS WILL PROVIDE -- SHOW THE ALPHA SYNUCLEIN BASED MODEL MAYBE MORE PARTICULAR. SO WHY DO WE NEED STANDARDIZATION? FOR SOMEBODY WHO IS FAMILIAR WITH ALPHA SYNUCLEIN BASED MODEL, THERE IS A CONFUSING ARRAY OF ANIMALS, INITIALLY GENERATED BY INDEPENDENT INVESTIGATOR FUNDED BY NINDS BUT MORE RECENTLY, THE ANIMAL MODEL INITIATIVE STARTED BY MICHAEL J. FOX FOUNDATION. THESE MODELS NEED TO BE WE SHOULD PROVIDE SOME GUIDANCE WHAT ARE THE MODELS CAPABLE OF AND GOOD FOR AND HOW TO USE THEM. I THINK THIS WILL FACILITATE REPLICATION AND COMPARATIVE ANALYSIS IN TERMS OF PRE-CLINICAL TRIALS. I THINK BECAUSE OF THE GRANT THIS COMES UNDER, THIS IS SOMETHING THAT CAN BE ACCOMPLISHED BY NINDS INITIATIVE. SO THERE ARE A MULTITUDE OF TARGETS EVALUATED IN ALPHA SYNUCLEIN MODELS. NOT JUST IN VIVO DYNAMICS OF ALPHA SYNUCLEIN METABOLISM BUT DOWN TO NEURODEGENERATION. H WILL HOLD SIGNIFICANT PROMISE FOR THERAPIES IN THE FUTURE. SO I'LL HAND OVER TO CLIVE TO TALK ABOUT THE IPS CELLS. >> THANKS VERY MUCH, MIKE. WE'RE GOING TO CONTINUE THE THEME OF MODELING. I WOULD LIKE TO POINT OUT MIKE (INAUDIBLE) MUTATION SO THEY MAY HAVE COMPENSATE VERY WELL FOR ABNORMALITIES IN IN SIGH SYNUCLEIN WHICH BRINGS ME TO OTHER MODELS. THIS PARTICULAR RECOMMENDATION WE TALKEDDED ABOUT SOMETHING THAT COMBINES THE THINGS DISCUSSED TODAY, BIG DATA AND NOVEL MODELS. THIS REPRESENTS COMPLEXITIES OF PARKINSON'S DISEASE AND DOWN SIDE ONE CAN IMAGINE DIFFERENT HUMAN GENOTYPES THROUGH MUTATIONS WHICH SEGREGATE OUT THIS POPULATION ONE WAY THEN THE OTHER DIRECTION WE HAVE HEARD ENVIRONMENTAL TOXINS. ENVIRONMENTAL TOXINS MAY CONTRIBUTE TO PARKINSON'S DISEASE SUCH AS STRESS, HEAD INJURY, I WILL TOUCH ON THAT AGAIN IN A MOMENT. WE HAVE A COMPLEX SERIES OF FACTORS SO IMAGINE IF YOU WERE UP IN THE ZONE HERE WITH GENOTYPE EXPOSED TO TOXINS, THIS PURPLE BOX REPRESENTS PARKINSON'S. FINALLY, THERE'S TISSUES. WE TALKED BRAIN, ALSO FEATURING SO IN THE JUST DOPAMINE NEURONS BUT THINKING TISSUES IN THIS DIRECTION. HUMAN CELLS ARE IMPORTANT IN THE CONTEXT OF MOUSE, SO I WOULD LIKE TO DISCUSS INDUCED PLURIPOTENT STEM CELLS THESE CELLS PROVIDE FOR THE FIRST TIME DISCOVER AD FEW YEARS AGO ABILITY TO LOOK AT THE DISH AT HUMAN CELLS CARRYING PARKINSON'S MUTATION, NOT JUST IN THE TERMS OF DOPAMINE NEURON BUT ALSO IN TERMS OF OTHER TUSH SHOE TYPES INCLUDING GUT AND WE CAN APPLY THEM AND GENE TYPE AND LOOK AT GENOTYPES AND SEE IF THIS MODEL IS CORRECT. IN TERMS OF VITRO AND TIE THAT TOGETHER WITH CLINICAL DATA FROM EACH INDIVIDUAL PATIENT. HERE IS MY WIKIPEDIA VERSION OF EMBRYONIC STEM CELLS. WE STARTED THE WHOLE FIELD. (INAUDIBLE) ISOLATED FIRST ISOLATED BY ANIMY FRIEND AND COLLEAGUE JAMIE THOMPSON, THESE ARE THE PLURIPOTENT EMBRYONIC STEM CELLS IN CULTURE, THEY CAN MAKE ANY TISSUE IN THE HUMAN BODY, ANY 240 TISSUES BY GIVING A COCKTAIL OF FACTORS AND MAKE NEURONS, DONE MEAN NEURONS EFFICIENTLY FROM THESE CELLS. A HUGE AMOUNT OF DISCUSSION OVER THE USE OF EMBRYONIC STEM CELLS, THE ETHICS OF COURSE CONFOUNDED, NEGATED, BY (INAUDIBLE) A COUPLE OF YEARS AGO FOR THE FINDING. OF INDUCED PLURIPOTENT STEM CELLS. WE CAN TAKE A SKIN CELL AND DO WITH BLOOD, WE CAN DO IT WITH HAIR FOLLICLE TISSUE, ALMOST WITH ANY CELL IN THE BODY AND HIT THEM WITH REPROGRAMMING FACTORS, KEY REPROGRAMMING FACTORS, REDUCING TO THREE OR FOUR WEEKS YOU GET INDUCED PLURIPOTENT STEM CELLS WHICH ARE IDENTICAL IN ALL ASPECTS TO EMBRYONIC STEM CELLS, IPS CELL CONFERENCES WILL ARGUE ABOUT DETAILS BUT ESSENTIALLY THEY'RE IDENTICAL WHICH IS QUITE REMARKABLE, IT REALLY SHOWS YOU EVERY CELL IN THE HUMAN BODY HAS THE SAME DNA, YOU REPROGRAM IT IT WILL GO BACK IN TIME TO AN EMBRYONIC STATE AND HERE WE HAVE IPS CELLS. THE BEAUTY IS WE CAN GENERATE CELLS FROM ADULT PARKINSON'S PATIENT UP TO 100 YEARS OLD ACHIEVEDDED NORMAL PATIENTS AND CONTROL PATIENT, THESE CELLS CAN BE REPROGRAMMED. NOW WE CAN MAKE BRAIN TISSUE DOWN THIS ROUTE AND DOPAMINE NEURONS FROM THE DISEASE PATIENT. THIS IS THE HUGE AM OF POWER TOLL THE ABILITY TO MODEL PARKINSON'S DISEASE. WHAT WE SHOWED ESSENTIALLY WAS THIS PAPER IBS CELLS FROM PARKINSON'S DISEASE SPORADIC PATIENTS. DOPAMINE NEURONS AND HERE YOU CAN SEE THE DOPAMINE NEURONS IN THIS FIGURE. DOPAMINE NEURONS FROM PARKINSON'S PATIENTS SURVIVE BETTER OR LESS WELL THAN CONTROL PATIENTS AND TURNED OUT THIS STUDY AND OTHERS MAKING THEM INTO DOPAMINE NEURONS YOU DON'T SEE -- TURNS OUT YOU HAVE TO STRESS THESE CELLS L SO THEY CAN INITIALLY MAKE DOPAMINE NEURONS WHICH MAKES SENSE GIVEN PARKINSON'S IS NOT A DEVELOPMENTAL DISORDER, THEY CAN MAKE THE DOPAMINE NEURON BUT I'LL MENTION TWO MORE PAPERS, TWO MORE IN THE FIELD, ONE KEY ONE THIS ONE FROM THE NIH CONSORTIUM, ETING UP AS 101 TO ARCLS AND ONE FOR PARKINSON'S DISEASE ESSENTIALLY THEY TOOK IPS CELLS FROM PATIENTS OF PARKINSON'S AND SHOWED THESE MITOCHONDRIAL DEFICITS. THOUGH KNOW AVERT CELL DEATH IN THIS MODEL IT WAS AFFINE TIME THEY SAW IN THE CELLS IN THE MITOCHONDRIA. SO AFTER THIS PAPER YOU'LL JUMP FORWARD TO PAPER THIS NOVEMBER WHERE THEY TOOK CELLS FROM A PATIENT WITH SYNUCLEIN MUTATIONS. THEY GREW THEM OUT IPS CELLS AND MADE TO DOPAMINE NEURONS, THE ANSWER WAS NO ON THEIR OWN BUT THEY DID AN INTERESTING EXPERIMENT WHICH GOES BACK TO MY BLOCK DIAGRAM AT THE BEGINNING, THEY TESTED -- CHALLENGED THE CELLS WITH PESTICIDES. ONE WAS PARAQUARTER WHICH IS A RISK FACT DOOR FOR PARKINSON'S AND WHILE CHALLENGING THE CELLS THEY WERE SENSITIVE TO THIS PARTICULAR STRESS, UNLIKE CONTROL COUNTER PARTS FROM NON-PARKINSON PATIENTS. TO LOOK AT TWO FACTORS WHICH LEAD TO (INAUDIBLE) AND CAME OUT WITH MEF-2 MECHANISM FOR THIS PROBLEM WHICH AGAIN BACK TO JOHN'S DISCUSSION, WE MADE A TARGET AND THESE ARE HUMAN DOPAMINE NEURONS FROM HUMAN PATIENTS CARRYING THE DISEASE FOR WHICH WE HAVE A PHENOTYPE. WE'RE GOING TO HAVE IMAGING DATA FROM THE PATIENTS, CLINICAL DATA FROM THE PATIENTS, AND NOW WE HAVE DOPAMINE NEURON SITTING IN FRONT OF YOU IN THE DISH WHICH I THINK IS VERY EXCITING. SO LAST SLIDE, I THINK BRINGS UP -- TOGETHER SOME OF THE DISCUSSION WE HAVE BEEN HAVING. I THINK THIS IS THE IDEA OF PERSONALIZED MEDICINE. SO AS I TOLD YOU WE CAN TAKE DISEASE PATIENTS, IN THAT PAPER FROM STEWART LIPTON AND (INAUDIBLE) THEY DID THE ANOTHER WHICH IS COMING NOW TO THE FOREFRONT. THEY TOOK THE SYNUCLEIN MUTATION LINE AND THEY TOOK THE MUTATION OUT OF PARKINSON'S LINE AND USED IT AS A CONTROL LINE SO THEY HAVE THE IDENTICAL GENERAL TICK BACKGROUND TO DOs PEOPLES IN. THIS IS THE WAY THE FIELD IS MOVING FORWARD TO TAKE OUT THE DEFICIT. REMEMBER I TOLD YOU ABOUT NEURONS, YOU CAN GET TISSUE TYPES NOW FROM IPS CELLS IN PARKINSON'S PATIENT. DOESN'T HAVE TO BE DOPAMINE NEURONS, CAN BE BRAIN STEM NEURONS, COULD BE (INAUDIBLE) AND WE HAVE A LOT OF DATA PUSHING DOWN THE ENDODERM ROUTE, WE CAN MAKE WHOLE GUT ORGANOIDS IN THE DISH AND LOOK AT LEAKYNESS AND SIGH NEW KLINE EXPRESSION IN THESE PATIENTS. THIS IS GOING TO CREATE NOVEL THERAPIES. ALWAYS GOING TO MAKE THE LINES, WE CAN MAKE OTHER TISSUE, CHALLENGE WITH STRESSES, RELATE TO THE BASIC AND CLINICAL DATABASES THAT WE HAVE BEEN TALKING ABOUT SO MUCH, BIG DATA, INCORPORATE IPS CELLS. I HOPE WE CAN LEARN MORE ABOUT DISEASE MECHANISMS USING THIS TECHNIQUE. I HAVEN'T MENTIONED CLINICAL TRANSPLANTATION BUT AS WE LEARN MORE ABOUT THESE CELLS, WE CAN OBVIOUSLY MAKE THEM INTO DOPAMINE NEURONS AND TRANSPLANT THEM IN THE STRIATUM TO LOOK AT MODULATIONS OF THE DISEASE AS WELL SO MANY DIFFERENT ASPECTS ENTERTAINED FROM THIS ONE TECHNIQUE. PERSONALIZED DRUG THERAPY, ONE WOULD IMAGINE THE FUTURE IF YOU HAVE A PATIENT YOU WANT TO TRY A DIFFERENT PARKINSON'S DRUG, YOU CAN TEST IPS CELLS AND DOPAMINE NEURONS FIST AND SEE IF THE RESPONSE IS WHAT EWE EXPECT BEFORE YOU GIVE THE DRUG TO THE PATIENT. THAT IS WHERE THEY'RE GOING IN HEART DISEASE BEFORE GIVING TO THE PATIENT. I THINK WE'LL END UP THERE IN NEUROSCIENCE AS WELL. SO I WOULD LIKE TO SUGGEST THIS LITTLE PYRAMID DESIGN AND TIE THESE SESSIONS TOGETHER. WE HAVE THE BASIC SCIENCE OF PARKINSON'S, WE USED TO RELY IN TRANSLATIONAL PART CELL LINES GIVING US IDEAS AND JOHN WILL TELL YOU FAR MORE SOPHISTICATED NOW, WE CAN USE THE ANIMAL MODELS, THEY PROVE TO BE VERY DIFFICULT BECAUSE ANIMALS ARE HUMAN BUT NOW WE HAVE IPSC CELLS TO GIVE ANOTHER PILLAR OF SUPPORT. ONE OF THEIR OWN IS NOT GOING TO BE BENEFICIAL BUT IF YOU MERGE TOGETHER AND USE THE INFORMATION, MORE WILL FIT TO THE TARGET AND GETTING TO CLINICAL TRIAL. SO I THINK NOW WE MOVE TO A PANEL DISCUSSION. >> THANK YOU CLIVE AND MICHAEL. I THINK THIS IS A REALLY CRITICAL AREA. I'LL START BY MAKING A COMMENT AND ASK MY PANELISTS TO CHIME IN. I THINK TRYING TO REALLY UNDERSTAND, THIS GETS BACK TO TRYING TO DEVELOP TOOLS MORE PREDICTIVE OF CLINICAL TRIAL RESULTS, A KEY HERE, SO FOCUSING ON WAYS THAT WE CAN CONNECT WHAT WE DO IN THE LAB WITH THESE TOOLS TO WHAT WE DO IN PATIENTS OR SEE IN PATIENTS IS ESSENTIAL. IPS CALL OFFERS US THE OPPORTUNITY TO REVERSE ENGINEER TRANSLATIONAL TOOLS SO MAYBE EVEN BECOME MORGUE POSSIBLE THE MAKE WHITE BLOOD CELLS FROM IPS CELLS SO SKIN BIOPSY TO CONTEMPLATE SAVING WHITE CELLS FOR PATIENTS, SO AFTER THE FACT POST HOCK WE CAN LOOK AT CERTAIN PATIENTS MAKE IPS CELLS AND LOOK AT WAYS TO DO PATIENT STRATIFICATION OR UNCOVER WAYS TO UNCOVER STRATIFICATION FOR FUTURE CLINICAL TRIAL WILL BE USEFUL AND WE'LL GO THROUGH EACH PANEL AND ASK THEM TO TALK ABOUT WHAT THEY THINK THE MOST IMPORTANT POINTS ARE. >> ONE THING THAT STRUCK ME LISTENING TO THE TALKS JUST NOW, CONCERN THE FACT THAT THE -- MUCH OF THE BIOLOGY WE'LL HEAR ABOUT LATER TODAY AND TOMORROW RELIES ON MOLECULES, TRAFFICKING WITHIN NEURONS. THAT PRESENTS PARTICULAR CHALLENGES TO HOW MOLECULES ARE TRAFFICKING THROUGH THE CELL IN TERMS OF MUTATIONS PRESENT IN THOsE CELLSn SO THE QUESTION IS WITH THE BRAIN INITIATIVE PUT FORWARD A LARGE NUMBEr OF TOOLS DEVELOPED THAt COULD BE UTILIZED TO ALLOW FOR MONITORING OF MOLECULAR DYNAMICS IN THE BRAIN IN MODEL SYSTEMS SUCH AS THE MOUsE SYSTEM YOU DESCRIBEDDED SO THE QUESTION I HAVE IS TO WHAT EXTENT CAN WE MONOPOLIZE ON THE BRAIN INITIATIVE TO BUILD BRAIN TOOLS TO FOLLOW MOLECULES NOT WITH IMMUNOHISTOCHEMISTRY LONG AFTER SOMETHING HAS HAPPENED IN THE ANIMAL BUT MORE REAL TIME SITUATION BOTTLE NECROSCOPY TYPE APPROACH TO LOOK AT AND DETAIL WHAT'S HAPPENING WITH ORGANELLES, MITOCHONDRIA,œET CETERA IN THE CONTEXT OF NOT ONLY ALPHA SYNUCLEIN MODEL VERSUS TOXIN MODEL OR OTHER GENETIC TYPES OF MODELS THAT MIGHT BE PUT FORWARD IN THE FUTURE. >> THAT'S INCREASINGLY POSSIBLE WITH TWO PHOTON MICROSCOPY AND MYRIAD OF REPORTERS THAT'S CERTAINLY ONE APPROACH THAT MADE IT POSSIBLE TO DO IN VIVO PHARMACOKINETICS SPECIFICALLY AT ACTION OF AGENT ON A PARTICULAR PATHWAY YOU GUY ALSO TALK ABOUT THAT MORE, SOUNDS LIKE THERE'S ADDITIONAL DESCRIPTIONS THERE IMAGING APPROACHES THAT ARE RELEVANT FOR ANIMAL MODELS THAT WILL BE USEFUL. >> TO FOLLOW UP ON THAT, THE NEXT LEVEL OF EXCITEMENT IN THE IPS FIELD IS TRANSPLANTATION IN ANIMALS. ONCE YOU DO THAT YOU CAN APPLY OPTO GENETICS TO STIMULATE NEURONS IN CONTEXT OF CIRCUIT IF YOU CAN GET THEM TO PLUG INTO THE CIRCUIT AND DOPAMINE RELEASE UPON STIMULATION, THERE ICE FAR MORE SOPHISTICATED MODELS ARE NOT THERE YET BUT USING CHIMERIC MICE THAT CARRY THE HUMAN CELLS, THEN YOU GET THE BLOOD BRAIN BARRIER, YOU GET SYSTEM ACTIVATION, WE HAVE HUMANIZED MICE WHICH HAVE A HUMAN IMMUNE SYSTEM. IF ONE COMBINES THAT WITH THE IPS TECHNOLOGY. SO THOSE ARE THE TOOLS THAT THEN THE BRAIN INITIATIVE CAN UTILIZE NOT MICE BUT HUMAN MICE THAT MIGHT BE POWERFUL TOOL FOR THE MOMENT WE NEED TO WORK ON THE TRANSPLANT SIDE. >> THERE'S PROBABLY PATIENTS LISTENING. I WONDER IF YOU CAN SAY A FEW WORDS ABOUT TRANSPLANTATION AT THERAPEUTIC STRATEGY. >> THAT'S A LONG TOPIC. THERE HAVE BEEN OVER 400 PATIENTS TRANSPLANTED WITH DOPAMINE NEURONS. THERE'S EXCITEMENT ABOUT IPS MAKING DOPAMINE NEURONS. RECONNECTION IN MY MIND OF THOSE CELLS. YOU PUT THEM IN THE STRIATUM ECTOPICALLY CAN THEY PRODUCE THE RIGHT SIGNALS TO GET BETTER EFFECT ON EL DOPA ALONE. NEW FETAL TRANSPLANT SERIES OF PATIENTS DONE IN EUROPE THAT MIGHT ADDRESS THAT ISSUE USING DIFFERENT FETAL TISSUE, SOPHISTICATED WAY TO GET THE DOPAMINE NEURONS BUT IT'S STILL CONNECTIVITY THAT'S A PROBLEM THAT NIGRAL STRIATAL TRANSPLANT THAT'S A CHALLENGE WE FACE WITH NEURAL TRANSPLANTATION IN PARKINSON'S TO GET THE CIRCUIT RIGHT. >> RICHARD, WHAT ARE YOUR THOUGHT? THE MOST IMPORTANT POINTS IN THIS TARGET ENGAGEMENT EFFICACY TOPIC? >> I AGREE WITH MIKE ANIMAL MODELS ARE KEYND I AGREE WITH CLIVE IMPORTANT THEM CELLS ARE IMPORTANT ALONG THE WAY, ONE THING THAT JUMPS TO MY MIND, THE ENVIRONMENT IN THE DISH IS DIFFERENCE THAN THE ONE IN THE BRAIN AND ONE HAS TO CONSIDER THE IN VIVO SCENARIO FOR DOPAMINERGIC NEURONS AND GROWTH FACTOR SUPPLY AND MEDIATING THE IPS CELLS IS NOT EQUIVALENT. JUST A WORD OF CAUTION ON THE IPS CELLS. >> IN VIVO TRANSPLANT MODEL ARE -- THERE'S LIMITATIONS TO WHAT YOU CAN PROJECT FORWARD AND MODELING STRONGER. THAT'S IN VIVO MAKING MINO BRAINS AND GETTING IN VITRO IN 3-D YOU NEED TO VASCULARIZE IT AS WELL. SO LOTS OF WORK TO DO TO MAKE IT A REAL THING. >> IT'S IMPORTANT ANIMAL MODELS ARE CLEARLY NOT HUMAN DISEASE, INCOMPLETE. WHILE WE TRY TO PERFECT THE ANIMAL MODEL, WE HAVE TO LOOK AT WHAT WE CAN STUDY AND LOOK AT IT GLASS HALF FULL THAN HALF EMPTY. A LOT L COMES FROM EVALUATING THE NOVEL THERAPIES, IN THESE ANIMAL MODELS DESPITE FLAWS. I KNOW (INAUDIBLE) TALK MORE ABOUT IT. DISEASE OCCURS THROUGH LONG TIME PERIOD. 12, 15 MONTHS, EXPENSIVE LONG TERM STUDY. ALLOWS POTENTIAL TO DO THIS IN SHORTER TIME FRAME. BECAUSE YOU CAN -- IT OCCURS TWO TO THREE MONTHS AFTER INNOCULATION. SO YOU CAN COME PRESS THE TIME FRAME. BUT IT'S IMPORTANT TO KNOW HOW MUCH THE SAME FEATURES OCCUR IN ALL DIFFERENT MODELS? PATHOLOGICAL FEATURES. COMPARED TO ANIMAL THAT NORMALLY DEVELOP A DISEASE OR HUMAN PD CASES FOR THAT MATTER IS ALSO IMPORTANT, THIS INTERROGATION OF THE ANIMAL MODEL WITH THE HUMAN DATA. >> I HAVE A QUESTION FOR THE PANEL BUT ALSO THE WHOLE GROUP IF IT'S OKAY WITH YOU. WE AGREE TO HAVE BETTER ANIMAL MODELS, LIMITATIONS IN THE TOXIC MODELS, TRANSGENIC MODELS THEY TAKE A LONG TIME, THEY HAVE AN ADVANTAGE THAT WE CAN SEE NO MOTOR SYMPTOMS IN ADDITION TO MOTOR SYMPTOMS. IF I ASK YOU I CAN GIVE A TRANSGENIC MONKEY MODEL THE DEVELOP ARRAIGNS GENIC MONKEY MODEL TAKES A LOT OF WORK. WHICH JEAN WOULD YOU LIKE TO SEE FIRST? ALPHA SYNUCLEIN, A 53T, (INDISCERNIBLE), WHAT WOULD BE YOUR GENE OF CHOICE? >> THAT WOULD BE INTERESTING. >> PARKINSON'S WOULD BE INTERESTING BECAUSE THE KNOCK OUT HUMAN PHENOTYPEPIN NULL NIGH -- BUT THE NULL MICE DOES HAVEN'T PHENOTYPE SO THERE'S IMPORTANT DIFFERENCES BETWEEN RODENTS AND MAN AT LEAST IN THAT SCENARIO. >> BUT EVERYBODY TALKS ABOUT ALPHA SYNUCLEIN. THE OTHER QUESTION I WOULD HAVE, WOULD YOU PREFER TO HAVE OVEREXPRESSION OF PROTEIN OR GENETIC EDITING SO YOU REPLACE ONE GENE FOR ANOTHER? >> PEOPLE HAVE INTRODUCED WILD TYPE SYNUCLEIN INTO PRIMATES USING VIRUS. >> I'M TALKING NON-MOTOR SYMPTOMS, I'M TALKING TRUE TRANSGENIC. >> I GUESS THAT'S A DIFFICULT ONE BUT MULTIPLE COPIES, COPY NUMBER INCREASE IN HUMANS DO CAUSE VERY SEVERE FORMS OF LEWI BODY DEMENTIA AN PARKINSON'S DISEASE, SO I THINK IF -- IT MAY TAKE LONGER THAN OVEREXPRESSING MUTANT BUT I WOULD IMAGINE BOTH OF THOSE WOULD WORK. >> PARKIN, I WOULD EXPECT YOU SAY TO ME ALPHA SYNUCLEIN OVEREXPRESSION. >> THANK YOU. >> I WANT TO COME TO YOU ABOUT ANAL MODEL AND THE PARADIGM BETWEEN TOXIN BASED MODEL AND ALPHA SYNUCLEIN MODEL. THIS IS SOMETHING WE HAVE TO BE VERY CAREFUL AS WE MOVE FORWARD IN DEVELOPING NEW MODEL BUT TRYING TO FIND WHAT ARE THE BEST MODEL TO STUDY, ESSENTIALRY BECAUSE EACH MODEL HAS VALUE AS LONG AS YOU ANSWER THE RIGHT QUESTION INTO IT. I'M COMING BACK MAYBELY TOXIN BASED MODEL. PERSONALLY USING THE NP -- I DON'T KNOW WHAT TOXIN P BASED MODEL MEAN EXCEPT THAT USUALLY THEY ARE SHOWN AS PEOPLE SEE THEM AS PURELY NIGRAL STRIATAL DOPAMINERGIC DEPLETION MODEL WHICH IS A MISCONCEPTION, U IN FACT THERE IS EVIDENCE FROM THE LITERATURE IF YOU DO LOOK CAREFULLY AT THE WAY -- IS THAT WORKING AS MUCH THE WAY THAT PEOPLE DELIVER THESE TOXIN CAN LEAD TO VERY DIFFERENT RESULTS. THAT IS SHOWN IN RODENTS, NON-HUMAN PRIMATES FOR MANY, MANY YEARS, DEPENDING HOW THE DRUG, MPTP, DRUGS ADMINISTERED OVER HOW LONG MANY, MANY MONTHS OF TIME, THIS LEADS TOE A DIFFERENT PATHOLOGY OF THE BRAIN THAN YOU SEE WITH ACUTE ADMINISTRATION OF TOXIC. AND WHEN YOU LOOK AT PATHOLOGY CLEARLY TAKE THE TIME AND DO CAREFUL ANALYSIS OF CELL MOUSE IN THE BRAIN. YOU CAN FIND MANY BRAIN REGIONS IN THESE ANIMALS THAT SHOW CELL DEATH. WE DON'T NECESSARILY AGGREGATE, I UNDERSTAND THAT THESE MODELS ARE NOT ONLY AGGREGATES BUT CELL LOSS IN AREAS OF THE BRAIN THAT ARE KNOWN IN PATIENTS TO DEGENERATE. SO THIS IS ANOTHER POINT WE NEED TO LOOK AT CELL LOSS, PARTS OF THE HUMAN BRAIN SHOW DEGENERATION I THINK IT'S IMPORTANT WE PAY ATTENTION TO THAT AND ALSO REALLY GO AND LOOK CAREFULLY AT HUMAN PATHOLOGY IS VERY IMPORTANT. >> THANK YOU FOR THAT COMMENT. THAT'S A VERY IMPORTANT APPROACH TO THESE MODELS AND HAVE A REALISTIC SENSE WHAT THEY CAN DELIVER BUT ALSO APPROACH THEM WITH THE SPECIFIC QUESTION IN MIND NOT THREING TO GET MORE OUT OF THE MIND THAN THEY CAN EVER OFFERFUL THANK YOU VERY MUCH, DAVE. >> I WOULD LIKE TO -- WHAT I THINK IS IMPORTANT POINT OF REASON TO TAKE CAUTION AND OVERINTERPRETTING THE IPSC AND NEURON MODELS DERIVED FROM STEM CELLS. IN OUR HANDS, THIS NEW TECHNOLOGY, IN OUR HANDS OBTAINING QUOTE NEURONS IN LABORATORIES REFERRED TO IN THE SLIDE PRESENTATION. THESE NEURONS DON'T RECAPITULATE GENUINE NEURONS OF IMPORTANTLY AT LEAST FROM OUR PERSPECTIVE FROM SEVERAL SOURCES SO FAR. WE HAVE NOT SEEN SMALL SYNAPTIC VESICAL RELEASE OF DOPAMINE FROM THESE CELLS. THE TECHNOLOGY IS SO NEW, AND I THINK WOULD BE WE'RE, RERECAPITULATE NEURONS. SYNAPTIC FUNCTION I DON'T THINK IT'S A VERY GOOD NEURON AT THIS POINT. ALPHA SYNUCLEIN IS INVOLVED IN REGULATION OF VESICLE FUSION DOPAMINE SECRETION BY SMALL SYNAPTIC VESICALES. IF THAT'S NOT OCCURRING PERHAPS IT'S NOT THAT SURPRISING THEY MAY NOT RECAPITULATE THERE'S MORE WORK THAT NEEDS TO BE DONE BEFORE WE DRAW TOO MANY CONCLUSIONS FROM NEURONS FROM STEM CELLS BECAUSE CONDITIONS ARE TOO NEW HAVEN'T BEEN WORKED ON VERY CAREFULLY. WE CAN COMPLETELY TRUST THEM AT THIS POINT. >> I AGREE BRAND NEW TECHNOLOGY, SO SUNNY KLINE MODELS IN MICE MUCH LONGER AND STILL HAVE A WHOLE LIST OF ISSUES IN THOSE MODELS. WE HAVE TO FATES IT, ISN'T A GREAT MODEL OF PARKINSON'S DISEASE; SPORADIC PARKINSON'S DISEASE IS NOT A GOOD MODEL. THESE NEURONS ARE MATURE TO A POINT BUT THEY PROBABLY NEED TAKE THE FIELD AS AN EXAMPLE, LIKE THE DIABETES FIELD, THEY FOUND YOU ACTUALLY NEED TO EXPOSE THE CELLS TO IN VIVO ENVIRONMENT AND FULLY MATURE. I THINK THE BRAIN CELLS FULLY MATURE THEM AND GHETTO MAYBE THEN SEE SPORADIC PHENOTYPES WITHOuT HAVING EXOGENOUS AGENTS. Q. I AGREE. IN VITRO WE CAN RECAPITULATE SYNAPTIC FUNCTION IN DOPAMINE NEURONS, NOT PERFECT BUT WE CAN GET SYNAPTIC VESICLES SO FAR IN VITRO WE'RE IN THE THAT FAR AWAY. >> THEY MAKE CARDIOMYOCITES BUTNATURE SO WE'RE STRUGGLING. AND THERE'S GOING TO BRING UP IACUK ISSUES BECAUSE WE HAVE TO IMPLANT MODULES IN HUMAN MICE, (INAUDIBLE) BECAUSE WE MADE A MOUSE 60% HUMAN. SO IT BRINGS UP IACUC ISSUES DOING CHIMERIC STUDIES. I'LL GO BACK TO MARINA'S POINT, SHE ASKED AT LUNCHTIME, SO I HAD ALREADY HAD TIME TO THINK ABOUT IT. PROBABLy WILD TYPE MONKEY OVEREXPRESSING WILD TYPE SYNUCLEIN WILL OVEREXPRESS -- YOU SAID PHENOTYPING, FEE KNOW COPYING SPORADIC, YOU HAVE LEWI BODIES WEPT DOWN THAT PATH WITH MONKEY OVEREXPRESSING SYNUCLEIN AND GOT IT AT REASONABLY LATE AGE, THAT WOULD BE AN OUTSTANDING MODEL TO BASE THERAPEUTIC APPROACHES ON. >> HARRY ORR FROM MINNESOTA, PERHAPS UNFAIR ONE PERSON FROM MINNESOTA ASKING ANOTHER. YOU HAVE THIS CONSENSUS MEETING. YOU COME UP WITH A REPORT. WHAT LINES ARE APPROPRIATE FOR PRE-CLINICAL STUDIES. YOU SEE RECOMMENDATIONS TO NIH THAT SUBSEQUENT APPLICATIONS SHOULD BE REVIEWED ACCORDING TO THESE CRITERIA? >> I THINK THAT THE -- IF YOU LOOK AT THE CLINICAL -- PRE-CLINICAL TRANSLATIONAL APPLICATIONS THAT -- UO-1s AND R-21 TYPES THAT GO TO THE IN HOUSE STUDY SECTIONS, THOSE ACTUALLY ARE FORMULATED WITH CONSULTATION OF NINDS PROGRAM STAFF. I THINK IT IS PROPER TO ADVISE PEOPLE ON CERTAIN SETS OF ANIMALS IF THEY'RE INTERESTED IN ALPHA SYNUCLEIN. THIS ACTUALLY IS ALREADY BEING DONE. I THINK SOMEWHAT LITTLE BIT MORE FORMALITY WILL HELP CLARITY AND REVIEW. >> I JUST WANT TO MAKE ONE POINT OF USING MICE. I THINK MOST OF US ARE USING C-57 INBRED MICE. I HAD JUST HAD A DEJA VU. I WAS TRYING TO MAKE A MODEL FOR STREP TOCOCUSS DISEASE, THE FIELD TOLD ME NO WAY YOU CAN'T MAKE A MOUSE SUSCEPTIBLE TO STREPCOCCI. I SAID WHICH MOUSE DID YOU USE? BLACK SIX. WE TESTED THREE DIFFERENT ONES AN SURE ENOUGH THE SECOND WAS ALREADY HIGHLY SUSCEPTIBLE. SO I THINK WE ARE NOT DEALING IN THE CLINIC WITH INBRED HUMANS BUT INBRED MICE. THERE ARE NOW GREAT TOOLS BEING DEVELOPED TO OUTBREDS AND P SO ON. WE SHOULD MAKE AN ATTEMPT TO LOOK AT THE GENETIC VARIATION IN MICE AND NOT JUST ONE INBRED STRAIN. HUMANS ARE NOT LIKE THAT. >> ONE LAST QUESTION. WE HAVE INTERACTED WITH A NUMBER OF COMPANIES WHO ARE FRUSTRATED WITH A MOUSE MODEL BUT ALSO HAVE RESERVATIONS ABOUT THE IPS MODELS. YOU DREW THIS NICE CLIVE WITH THREE PILLARS, BUT ULTIMATELY A DECISION HAS TO BE MADE I KNOW PANES ARE WILLING TO BAIL ANT MOUSE MODELS AND BASED ON IPS RESULTS AND MAYBE HUMAN GENETIC RESULTS MOVE SOMETHING FORWARD. I WAS JUST CURIOUS FROM BOTH OF YOU, IF YOU HAVE DISCREPANT RESULT WHICH IS DO YOU BELIEVE OR WHAT IS YOUR THOUGHT ABOUT THIS? >> I PERSONALLY BELIEVE WHAT OCCURS IN AN IMPACT TISSUE. ANOTHER THING IF WE TIE THAT INTO WHAT HAPPENS IN HUMAN DISEASE, THAT'S THE IMPORTANT POINT. SOMETIMES THE CHALLENGE IS NOT DISCOVERING THERE'S ABNORMALITY IN YOUR MOUSE. ABNORMALITY RELATES TO WHAT HAPPENS IN HUMAN PATIENTS. AND I THINK IF WE CAN DO THAT, YOU ARE ON SOLID GROUND, I DON'T CARE WHETHER YOU'RE USING ANIMAL MODELS OR IPS CELLS. >> GLAD YOU DIDN'T SPIN ON THAT DIRECT QUESTION. IF I WAs A DRUG COMPANY I HAD TEN DRUGS I WAS GOING TO MOVE FORWARD, CELL LINES, MOUSE AN IPS AND FIVE WERE IN ONE AND NOT THE OTHER, (INAUDIBLE) ALL THREE AND MOVE THAT FORWARD. >> WITH THAT I THINK WE'RE ENDING. >> I WOULD LIKE TO THANK OUR PANEL. [APPLAUSE] >> OUR PRESENTERS. THANK YOU VERY MUCH. WE'RE GOING TO TAKE A 20 MINUTE BREAK. RECONVENE AT 3:20 WITH A PRESENTATION BY RICHARD YOULE. 20-MINUTE BREAK. WE'RE INTO THE LAST COMPONENTS OF TRANSLATIONAL RESEARCH SESSION. WE'LL HAVE TWO PRESENTATIONS AND THEN TWO PANEL DISCUSSIONS. SO IF YOU DON'T MIND, THERE ARE ENOUGH PEOPLE BACK WE'LL GET STARTED, INVITE OUR FIRST SPEAKER UP, RICHARD, YOU WILL -- I KNOW I SAW YOU, THERE YOU ARE. RICHARD YOULE FROM THE NINDS WILL BE THE NEXT SPEAKER, RICHARD. SO WADE HARPER AND I WILL COVER THE NEXT SESSION THAT COVERS THREE CLOSELY RELATED TOPICS. HOW DO YOU ADVANCE THE SLIDES? DO WE DO THAT? SO WE WILL COVER TOPICS OF THE IMPORTANT TOPIC OF TO DEVELOP TREATMENTS THAT ALTER THE COURSE OF DISEASE PROGRESSION WE NEED A BETTER UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF PD AND HOW WE MOVE FORWARD IN DRUG KISS DISCOVERY WITH OUR CURRENT UNDERSTANDING. THESE ARE OUR THREE POINTS WE'RE GOING TO COVER. THEY HINGE TO WHAT EXTENT ARE THERE UNIFYING HYPOTHESES AMONG PROPOSED PD ETIOLOGIES. AND NUMBER NINE, FIRST I'LL TALK ABOUT IMPORTANT TO INVESTIGATE THE RELATIONSHIP BETWEEN ALPHA SYNUCLEIN MISFOLDING AND MITOCHONDRIAL FUNCTION TO UNDERSTANDING PATHWAY OVERLAP. SO AS WE KNOW WELL, PARTICULARLY THIS MORNING THERE'S GENETIC AND PATHOLOGIC EVIDENCE FOR SYNUCLEIN, ALPHA SYNUCLEIN CAUSING PARKINSON'S DISEASE. THERE'S ALSO GOOD EVIDENCE THAT MITOCHONDRIAL DAMAGE ACCUMULATION IS LINKED TO PARKINSON'S DISEASE. THERE'S GENETIC EVIDENCE, PINK 1 KINASE, AUTOSOMAL RECESSIVE, HIGH PENETRANTS MONOGENIC CAUSE OF PD, PARKIN I'LL GET INTO THAT'S LINKED TO PINK 1 AND MITOCHONDRIAL DNA POLYMERASE THAT REPLICATES MITOCHONDRIAL DNA CALLED POLL G, THIS MUTATIONS IN MAN IN PULL G LEADS TO EL DOPA RESPONSIVE PARKINSONISM, THERE'S PATHOLOGIC EVIDENCE OF COX # OXIDASE, IT IS A MITOCHONDRIAL ENZYME AND THEN THERE'S ALSO MITOCHONDRIAL DNA DELETION ACCUMULATION IN AUTOPSY BRAIN AND SPORADIC PD. SO THE QUESTION IS, WHAT EXTENT THEY OVERLAP. AND THE GENERAL THEME OF THIS TALK IS GOING TO BE TO WHAT EXTENT DO THE MANY DIFFERENT GENETIC CAUSES OF PARKINSON'S DISEASE OVERLAP. ONE EXAMPLE, I WANT TO MENTION THIS ONE I ALLUDED TO, AUTOSOMAL RECESSIVE, LOSS OF FUNCTION MUTATIONS IN MAN THAT LEAD TO PD EARLY ONSET. THERE WAS A BREAK THROUGH IN DROSOPHILA GENETICS WHEN THAT SHOW THE MITOCHONDRIA IN THE PINK 1 KNOCK OUT SLIDE ARE DISRUPTED. THERE'S NORMAL DISRUPTION AND IF YOU LOOK AT THE PARK AND NULL FLY, THEY'RE IDENTICAL PHENOTYPE TO THE PINK KNOCK OUT SLIDE. IF YOU CROSS TOGETHER, DOUBLE KNOCK OUT SLIDE IT'S NO WORSE. THIS IS GENETIC EVIDENCE OF EPISTASIS THAT INDICATES THOSE TWO GENE PRODUCTS WORK IN THE SAME PATHWAY. THERE IS GOOD GENETIC EVIDENCE THESE WORK IN THE SAME PATHWAY. IF YOU DAMAGE MITOCHONDRIA THE KINASE PINK 1 ACCUMULATE ON THE MITOCHONDRIA AND RECRUIT THE LIGASE FROM THE CYTOSOL TO THE MITOCHONDRIA AND LEAD O ACCUMULATION OF MITOCHONDRIA SO SUGGESTING CONTROL PATHWAY VALIDATED BY DMITRI KRAINC WHO PROBABLY ISN'T LISTENING BUT HE'S STUCK IN CHICAGO. HE SHOWED IN HUMAN IPS CELLS THIS PATHWAY WORKS FOR PINK 1 RECRUIT PARKEN AND SHOWED THAT U BECOMES NEURONS DRIVE PIPING 1 MUTANT PATIENTS FAILED TO PERFORM THIS BIOCHEMICAL (INAUDIBLE). SO GOING FORWARD TO WHAT EXTENT DOES SYNUCLEIN MISFOLDING OVERLAP WITH MITOCHONDRIAL DAMAGE, MAYBE COMPLETELY INDEPENDENT DISEASES THAT'S IMPORTANT TO KNOW FOR PATIENT STRATIFICATION OR PERHAPS APPROXIMATE FA SYNUCLEIN MISFOLDING IMPACTS THE MITOCHONDRIA OR IT IMPACTS, PERHAPS THEY BOTH INDEPENDENTLY IMPACT DOWNSTREAM MYSTERIOUS STEP. SO WHAT DOES ALPHA SYNUCLEIN DO? WHATEVER IT DOES IT LEADS TO NEURON TOXICITY MAYBE A DOWNSTREAM CONSEQUENCE OF MITOCHONDRIAL DAMAGE. LIKE ROB EDWARDS ON THE BASIC GROUP, HE HAD ANANIAS PAPER SHOWING ALPHA SYNUCLEIN IMPACTS MITOCHONDRIAL ACTIVITY BUT THIS IS STILL NOT KNOWN TO BE THE PATHOPHYSIOLOGIC FUNCTION OF ALPHA SYNUCLEIN. MITOCHONDRIAL IMPAIRMENT AND SYNUCLEIN. ONLY A SUBSET OF THE PINK 1 PARACRINE PATIENTS, NOT A LOT TO AUTOPSY BUT SOME DO, SOME DON'T DISPLAY LEWI BODIES SO IN THE LIKELY THIS IS CAUSING SYNUCLEIN MISFOLDING OR YOU WOULD SEE HIGHER PEN TRANSOF LEWI BODIES UNLESS ALPHA SYNUCLEIN IS TOX UPSTREAM LEWI BODY FORMATION SO YOU IMAGINE A SON CONVOLUTED SCENARIO ARE IT CAUSED OLIGOMERS THAT DON'T GO TO LEWI BODIES. THEN LASTLY, THIS IS AN INTERESTING POINT THAT CAME OUT FROM THE DOUG TURN BALL GROUP IN NEW CASTLE. I MENTIONED THIS MITOCHONDRIAL LEWI BODY PATHOLOGY. THERE ARE HINTS OF LINKS BETWEEN THE TWO. TO KNOW THE EXTENT THERE'S GENETIC OVERLAP BETWEEN ALPHA SINUCLIEN TOXICITY IN THE PINK 1 PATHWAY OR EPISTASIS BETWEEN ALPHA NUCLEUS TOXICITY IN GENETIC MITOCHONDRIAL DAMAGE LINKED TO GD SUCH AS POLL MUTATION IN MICE. WE HAVE TO EXPAND THE LINK BETWEEN SUNNY KLINE AND MITOCHONDRIA TO OTHER GENETIC FORMS OF PARKINSON'S DISEASE SO ANOTHER RECOMMENDATION IS TO DEVELOP A THOROUGH UNDERSTANDING OF TARGETS AND PATHWAYS WITH PATHOGENESIS AND PATHOPHYSIOLOGY OF PD WITH THE EMPHASIS ON VALIDATED HUMAN GENETICS AND BIOLOGY. SO I WANT TO POINT OUT SOME OF THE IMPORTANT PAPERS AND LITERATURE, THERE'S SCORES SAYING LOCK 2 DOES THIS, SYNUCLEIN DOES THAT. WE NEED MORE VALIDATED ASSESSMENT, HERE IS PAPER FROM THE THING GROUP, CUMULATED NEURON TOXICITY IN VITRO AND THEY SHOW THAT MUTATION IN LAR TWO PROCEED TO LOSE NEURONS, INTERESTINGLY IF YOU ELIMINATE ALPHA SYNUCLEIN OR ALPHA BETA GAMMA SYNUCLEIN THERE'S LESS SOCK AT THIS SOYTIVE SO THIS IS AN EPISTASIS EXPERIMENT IN THE BIOLOGY OF NEURONS SHOWING GENETIC LINKAGE BETWEEN TOXICITY OF THESE TWO, THAT RELATES TO A NICE PAPER IN NEURON BEING HIGH WHERE HE SHOWED SEVERAL YEARS AGO IF YOU COMBINE ALPHA SYNUCLEIN MUTATIONS IN ALREADY 2 MUTATIONS YOU GET SYNERGISTIC TOXICITY TO NEURONS AND YOU ALSO GET SYNERGISTIC DAMAGE TO MITOCHONDRIA. I WANT TO POINT OUT IT'S NOT ALL MITOCHONDRIA YOU CAN FIND PAPER, HERE IS NICE PAPER IN VIVO IN THE FLY BY (INAUDIBLE) GROUP LOOKING AT NORMAL DISTRIBUTION OF LYSESOMES HERE BUT IN A LARK 2 MUTATION GREATRY DISRUPTED LYSESOMES. SO LYSESOMES -- LYSOSOMES IS THE ANSWER SO HE LOOKED AT GOLGI APPARATUS, THIS IS A NORMAL GOLGI APPARATUS BUT IF YOU EXPRESS MUTANT SYNUCLEIN YOU DISRUPT THE GOLGI APPARATUS INTERESTING IN THE WILD TYPE MOUSE OR LARK 2 HETEROZYGOTE BUT IF YOU OVEREXPRESS LARK 2 KNOCK OUT MOUSE YOU DON'T DISRUPT GOLGI SHOWING SYNERGISM BETWEEN THE TWO AT A DIFFERENT SUBCELLULAR ORGANELLE SO THIS POINTS OUT TO THE PROBLEM, NEEDS TO BE RESOLVED, VARIOUS INTRACELLULAR EFFECTS OF LARK 2 MUTATION IN ALPHA SYNUCLEIN, WE DON'T KNOW THE PRY MAIM UPSTREAM EFFECT OF EITHER ONE, WHAT'S THE PROXIMAL ACTIVITY YOU CAN IMAGINE LARK 2 DOES X, X DOES Y AND BRANCHES OUT PHENOTYPES IN CELL BIOLOGY, NOT SO IMPORTANT TO BE OUT THERE AS RIGHT PROXIMAL TO LARK 2. WE NEED BETTER ASSESSMENT OF THOSE. THEN EXPANDING BEYOND LARK 2 SYNUCLEIN TO MORE RECENTLY IDENTIFIED RISK FACTORS LIKE GBA AND ANOTHER MONOGENIC ATP 13A 2 LOCALIZED TO THE LYSOSOME. TRAFFICKING BPS 35 IS DOMINANT CAUSE OF PD THERE ARE RECENT PAPERS LINKING THESE BY DMITRI KRAINC LINKING TO OTHER KNOWN PATHWAYS. BUT THIS NEEDS TO BE BETTER VALIDATED IN ANIMAL MODELS LEAD TO A BETTER UNDERSTANDING OF HOW THEY CONNECT WITH ONE ANOTHER, PINK 1 PARKIN IN AT THAT TIME WAY ASSESSMENT. THAT LEADS TO WHAT WADE WILL TALK ABOUT, WE NEED TO DEVELOP TOOLS AN TECHNOLOGIES FOR MEASURING PATHWAY ARCHITECTURE AND FLUX. >> THANKS. I'M GOING TO TELL YOU ABOUT WHAT WE TALKED ABOUT IN THE GROUP ABOUT DIFFERENT TOOLS AND TECHNOLOGIES WE MIGHT BE ABLE TO USE TO ADVANCE OUR UNDERSTANDING OF THE NETWORKS THAT ARE INVOLVED IN PD. SO AS YOU CAN SEE HERE, THERE'S NUMEROUS DIFFERENT APPROACHES DISCUSSED IN OUR GROUP. CONCERNING TECHNOLOGIES MAY NOT HAVE BEEN APPLIED THUS FAR BUT PERHAPS TO OTHER SYSTEMS THAT MIGHT BE USEFUL AS WE MOVE FORWARD TO UNDERSTAND AND SORT OF A SPECIFIC WAY HOW PROTEIN PATHWAYS AND DYNAMICS OF ORGANELLES AS RICHARD MENTIONEDDED PD HAS CONNECTIONS CAN WITH ORGANELLE OR TRAFFICKING IN MANY DIFFERENT WAYS SO HOW CAN WE USE THESE DIFFERENCE TOOLS TO LOOK AT NETWORKS AND PATHWAY? >> JUST TO THE START I WANT TO TALK GENERAL TERMS HOW WE THINK ABOUT PROTEIN PATHWAYS. HERE I'M SHOWING TWO PARKINSON'S DISEASE GENES, DISEASE GENE 1 AND 2, HYPOTHETICAL EXAMPLES. EACH TWO GENES INTERACTS WITH A COMMON SET OF PROTEINS INDIVIDUALLY. AND PERHAPS THEY MAY SHARE COMMON INTERACTING PROTEINS. AND HAVE SOME CONNECTIVITY DOWNSTREAM BUT EACH OF THOSE INTERACTING FROM TEENS THAT BIND TO ALSO HAVE OTHER PROTEINS IN THE CELL THEY INTERACT WITH. SO YOU CAN IMAGINE DEVELOPMENT OF A NETWORK OF GENES THAT AFFECT VARIOUS ASPECTS OF CELL BIOLOGY VESICLE TRAFFICKING, MITOCHONDRIAL HELP, ET CETERA SO I THINK ABOUT THESE IN TWO WAYS, THERE'S PRIMARY INTERACTION NETWORK AND ALSO SECONDARY INTERACTIONS. THAT HAVE IMPACT IN TERMS OF DETERMINING THE STATE OF THE CELL. SO YOU CAN IMAGINE MUTATION AND PARTICULAR PARKINSON'S DISEASE GENE CALL IT PARKINSON'S DISEASE GENE 1. IN THE CONTEXT OF MUTATION THE NETWORK IS ALTERED IN A PARTICULAR WAY. THE WAY THAT NETWORK IS ALTERED CAN THEN LEAD TO CHANGES IN FLUX OR TRAFFICKING OF DIFFERENT KINDS OF ORGANELLES OR OTHER MOLECULES. THAT CHANGES THE STATE OF THE CELL IN TERMS OF ABILITY TO DO THE THINGS IT NEEDS TO DO IN ORDER TO SURVIVE AND BE A HAPPY CELL. SO WHAT WE WANT TO BE ABLE TO DO IN A CONTEXT OF SYSTEMS ANALYSIS, OR NETWORK ANALYSIS IN PARKINSON'S DISEASE IS UNDERSTAND HOW NETWORK DYNAMICS IS ALTERED WITH CERTAIN DISEASE MUTANTS AND HOW THE STATE OF THE CELL IS ALTERED. HOW THE ABILITY OF THE CELL TO DEAL WITH STRESS FOR EXAMPLE IS ALTERED. THAT MIGHT BE DIRECTLY IMPINGED UPON BY HOW ORGANELLES TRAFFIC IN THE CELL. COUPLE OF DIFFERENT IDEAS HERE ABOUT USING VARIOUS KINDS OF APPROACHES, SOME OF WHICH ARE NEWLY EMERGING APPROACHES PARTICULARLY TO LOOK AT DYNAMICS IN CELLULAR SYSTEMS INCLUDING CELL SYSTEMS SUCH AS UPS CELLS THAT HAVEN'T BEEN UTILIZED UTILIZED IN THIS CONTEXT QUANTITATIVE PROTEOMICS SINCE TO GET A GRASP OF WHAT'S GOING ON WITH A PARTICULAR NETWORK AND HOW A MUTATION IN PARKINSON'S DISEASE EFFECTS THE STATUS OF THAT NETWORK, TO UNDERSTAND QUANTITATIVELY, MANY STUDIES DONE BEFORE THAT LED TO IDENTIFICATION OF INTERACTING PROTEINS FOR EXAMPLE, LOOKED IN A QUALITITATIVE WAY. LOOKING IN A QUANTITATIVE WAY IS WHAT'S NEEDED TO UNDERSTAND HOW THE MOLECULAR INTERACTIONS ARE ALTERED. A KEY POINT HERE IS YOU CAN DO THIS WITH OR WITHOUT PARKINSON'S DISEASE MEANING PROTEIN, YOU CAN LOOK AT DIFFERENT STIMULI, EXAMPLE THE CELLS AFFECTED BY ER STRESS OR OTHER KINDS OF STRESS. YOU CAN LOOK AT CANDIDATE DRUGS TO TRY TO FIGURE OUT IF THOSE AFFECT THE NETWORK. LIKEWISE, SO THAT DISCUSSION CONCERNS THE PRIMARY INTERACTING PROTEINS. YOU CAN ALSO APPLY THE SAME APPROACHES TO THE GLOBAL PROTEOME TO LOOK SEEABLELY LARGER SCALE NETWORKS ARE AFFECTED IN A QUANTITATIVE MANNER. ESSENTIALLY USING THE SAME KINDS OF APPROACHES. FINALLY ONE PROBLEM WITH PROTEOMIC TYPES OF APPROACHS WE'RE TALKING ABOUT IS THAT IT'S NOT A SINGLE CELL APPROACHES, YOU'RE MEASURING ENSEMBLES OF CELLS. SO IPS FOR EXAMPLE WITH HIGH HETEROGENEITY OR FISH U SHOES, HIGH -- TISSUES HIGH HETEROGENEITY YOU'RE UNABLE TO EFFECTIVELY LOOK AT SPECIFIC CELLS AND WHAT'S HAPPENING IN INDIVIDUAL CELLS. SO ONE OF THE OTHER IMPORTANT ASPECTS GOING FORWARD IS TO USE THE POWER OF MYCLOSESCOPY TO DIG -- MICROSCOPY TO DIG INTO HOW NETWORKS ARE CHANGING. A PARTICULAR USEFUL APPROACH INVOLVES THE FLUX MEASUREMENT ASSAYS WHERE PHOTO ACTIVATEABLE OR PH SENSITIVE REPORTERS ARE USED REAL TIMING THAT HOW NETWORKS ARE CHANGING, IN RESPONSE TO A MUTATION IN A PD GENE. ALL THIS IS TECHNOLOGIES SUMMARIZED HERE ARE USEFUL WHEN APPLIED TO THE LARGER SCALE PROBLEM. HOW DIFFERENT PARKINSON'S DISEASE GENES AFFECT DIFFERENT COMPONENTS OF SIGNALING SYSTEMS AND CAN WE LEARN MORE ABOUT THE SYSTEMS BY LOOKING AT THEM FROM THE SYSTEMS POINT OF VIEW. SO THIS SLIDE SUMMARIZES THE GENOMICLY ENCODED FLUBBING AND PATHWAY REPORTERS, IN CELL LINES AN SYSTEMS AND ALLOW US TO LOOK IN DETAIL. HOW ORGANELLES TRAFFIC. WE NEED TO ENCOURAGE PHYSIOLOGICALLY AND GENETICALLY DEFINED CELL SYSTEMS, A LOT OF WHAT'S DONE BEFORE IS OUT OF CONTEXT FROM THE DISEASE. SO WE NEED TO ADDRESS THAT ISSUE. WE THINK THERE'S OPPORTUNITIES USING HIGH RESOLUTION SUPER RESOLUTION IMAGING TECHNOLOGY TRAFFICKENING NEURONS WITH DIFFERENT COMPONENTS. SO I WANT TO NOW SPEAK BRIEFLY ABOUT ANOTHER COMPONENT OF THE PROBLEM. IN TERMS OF HOW YOU USE NETWORKS THE LOOK FOR DRUGS. CAN WE USE PATHWAY ANALYSIS AND MODEL SYSTEMS TO ACCELERATE TARGET AND DRUG DISCOVERY THAT'S THE CENTRAL POINT OF THE TRANSLATIONAL APPROACH OUR PROP GROUP FOCUSED ON. SO AS RICHARD MENTIONED YOU HAVE DOMINANT MUTANTS AND RECESSIVE MUTANTS. FOR DOMINANT WE HAVE TO THINK ABOUT HOW TO REMOVE THE TOXIC PROTEIN OR BUT PASS TOXICITY. FOR SUCCESSIVE WE NEED TO ACTIVATE MUTANT ALLELES TO RESCUE PHENOTYPES SO THERE'S A COUPLE OF DIFFERENT METHODS BEING LOOKED AT NOW. IN TERMS OF BYPASSING TOXICITY IS YOU HAVE ANTI-SENSE OLIGONUCLEOTIDES IN PHASE 1 CLINICAL TRIALS FOR SPINAL MUSCULAR ATROPHY SMA. THEN THERE'S ALSO PRE-CLINICAL DEVELOPMENT OF ANTI-SENSE OLIGONUCLEOTIDES IN,LS AT DOMINANT GAIN OF FUNCTION TYPE PROTEINS SO THIS IS WORK IN UNFANCY, THERE'S WORK A LOT TO BE DONE BUT IT DOES HOLD PROMISE PERHAPS GETTING RID OF TOXIC PROTEINS. THERE'S LARGE STUDY IN THE PAST TO GET RID OF AGGRAVATED PROTEIN S. AND NUMEROUS MOLECULES PUT FORWARD, INCLUDING MOLECULES PUT FORWARD BY THE FINKBEINER LAB. SO THERE'S CLEARLY EFFORT IN THIS REGARD BUT IT'S NOT LIKE THIS HAS TAKEN THE NEXT STEP O THE CLINIC. SO THERE'S STILL MUCH TO BE DONE TO FIGURE OUT IF YOU CAN HARNESS THE POWER OF AUTOPHAGY TO THE REMOVE THESE KINDS OF AGGRAVATED PROTEINS. SO ONE IDEA I'LL TALK ABOUT BRIEFLY INVOLVE USE OF YEAST MODEL SYSTEM IN THE LAB TO LOOK FOR MOLECULES TO REVERSE TOXIC EFFECTS OF ALPHA SYNUCLEIN, IF YOU RECEIVE PROSES IT IN YEAST YOU GETTING A GATED PROTEINS THAT CAUSES PHENOTYPES IN YEAST THAT LEAD TO CELL DEATH. THEY CAN DO A MOLECULE SCREEN THAT BYPASS THE TOXICITY. YOU CAN SEE HERE YOU DOPE GET THE TOXIC FORMS OF THE PROTEIN, ALPHA SYNUCLEIN HERE, MORE DIFFUSE PATTERN YET YOU DON'T DEGRADE SYNUCLEIN EITHER SO IT'S NOT DEGRADED AS FAR AS WE CAN TELL BUT IT DOES APPEAR TO BYPASS THE TOXIC EFFECT OF THE SYNUCLEIN EXPRESSION IN YEAST. TURNS OUT THE SAME MOLECULE WORKS IN NEURONS AS WELL AS HUMAN DOPE DOPAMINERGIC URINES TO REVERSE TOXICITY SO AT THIS COVER MOLECULES THAT TURN OUT TO WORK IN CELLS. THE POWER IS YOU CAN USE THE POWER OF YEAST MR. JENKINS: TICK TO IDENTIFY GENES TARGETED BY THE MOLECULE AND UNDERSTAND HOW THEY ARE PLACED TO A PARTICULAR PATHWAY. AND IT TURNS OUT THAT THE MOLECULE THAT WAS IDENTIFIED HERE THIS NAV 2 MOLECULE ACTUALLY IS SOMEHOW ACTIVATING A UBIQUITIN LIGASE INVOLVED IN ENDOSOMAL TRAFFICKING. SO SOMEHOW THIS MOLECULE IS ABLE THE BYPASS THE TOXIC EFFECTS OF ALPHA SYNUCLEIN BY AFFECTING FLUX THROUGH THIS ENDOSOMAL TRANSPORT NETWORK. NOW, YOU CAN ALSO MODEL THIS IN IPS CELLS SO THE PHENOTYPES ARE IDENTIFIED IN YEAST INCLUDING VARIOUS ER DYSFUNCTION, ET CETERA, CAN BE REVERSED BY NAV 2. ALSO BY OVEREXPRESSION OF UBIQUITIN LIGASE, THE HUMAN ORTHO LOG OF THE YEAST GENE IDENTIFIED SO THAT WAS ABLE TO BE DONE IN YEAST CELL -- SORRY IPS CELLS, CARRYING AN ALPHA SYNUCLEIN MUTANT. SO THIS SUGGESTS THAT YOU MIGHT BE ABLE TO USE PATIENT DERIVED IPS CELLS AS A TOOL FOR EXAMINING PHENOTYPES USING THE MODEL SYSTEMS. THEN THERE'S ALSO THESE RECESSIVE MUTANTS, RICHARD TALKED ABOUTPIN PATHWAY SO THERE'S SOME PROGRESS BEING MADE IN THE IDENTIFICATION OF SMALL MOLECULE ACTIVATORS, THERE'S THE POSSIBILITY OF IDENTIFYING SMALL MOLECULES THAT ACTIVATE THIS CLOSED INACTIVE FORM OF PARKEN PERHAPS SORT OF PRESERVED IN MUTANT FORMS PRESENT IN HUMANS. SO GOING FORWARD WITH THESE DIFFERENT TARGETING APPROACHES, IT MAYBE INTERESTING TO SUPPORT NOVEL MODEL SYSTEMS FOR DRUG DISCOVERY, THIS CAN PERHAPS BE MADE FASTER THAN DOING APPROACHES IN IPS CELLS FOR EXAMPLE. I SHOULD POINT OUT THE FINKBEINER LAB ESTABLISHD A AUTOMATED MICROSCOPE PLATFORM FOR ALLOWING IMAGING FOR (INAUDIBLE) FLUX IN THE AND HITS FOLDED PROTEIN TURN OVER SO IT MAYBE POSSIBLE BY MERGING HIGH CONTENT IMAGINGENING A SCREENING FORMAT TO LOOK AT IPS CELLS AND LARGE NUMBERS OF DRUGS IN THE FUTURE. ALSO LARGE SCALE GENETIC SUPPRESSOR ENHANCER STUDIES ONGOING IN THE DROSOPHILA IN PINK AND PARKEN PATHWAY. JUST TO END ON THIS, YOU CAN IMAGINE A SITUATION WHERE FROM RICH'S WORK YOU HAVE GENOME WIDE RNAi TO LOOK AT PARKEN STREAM AUTOPHAGY SO WE HAVE ENHANCERS OFPEN, YOU HAVE WORK FROM (INDISCERNIBLE) LAB CURRENTLY UP PUBLISHED WHERE HE'S DUNGEON TUCK SCREENS AT PINK AND PARKEN GENETIC MODIFIERS AND DROSOPHILA AND GLOBAL PROTEOMICS STUDY MENTIONED HERE. SO THE OVERLAP BETWEEN THE PARTICULAR PARTICULAR DATA SETS PROVIDE CANDIDATES TO LOOK FORWARD IN TERMS OF DOWNSTREAM EFFECTS THAT YOU MIGHT BE ABLE TO BYPASS OR ACTIVATE WHATEVER IS GOING WRONG IN THE PARKEN AND PIPING SITUATION. SO WITH THAT WE'LL GO DIRECTLY TO THE PANEL DISCUSSION. >> SO AS WITH THE LAST SESSION I THINK WE'LL START BY ASKING FOR ANY COMMENTS OR ADDITIONAL INSIGHT FROM THE GROUP HERE. JOHN. >> A MS. TAKE -- I THINK CLEARLY WE MADE PROGRESS WITH REGARD TO A PATHWAY WITH REGARD TO THE RECESSIVE PD GENES IS DEFINITIVE; WE UNDERSTAND THE PROCESS AND I THINK ONE CAN IMAGINE THAT THE DISEASE IS CAUSE BECAUSE DOPAMINE METABOLISM CAUSES MORE MITOCHONDRIAL DAMAGE IN THOSE CELLS MIGHT BE ONE REASON, BUT IT'S CLEAR WE HAVE A PATHWAY WITH REGARD TO THE DOMINANT MUTATIONS IT'S MUCH LESS CLEAR AND I THINK WE HAVE NOT YET REACH AD SITUATION WHERE WE UNDERSTAND WHAT ALL THE COMMON FEATURE OF ALL THE MUTATIONS, WHAT COMMON FEATURE OF ALL THE MUTATIONS IS IN THE SAME LEVEL OF DETAIL. THAT'S CLEARLY SOMETHING WE HAVE GOT TO DO. I THINK THERE'S EMERGING CONSENSUS THAT IT IS AUTOPHAGY WHICH OF COURSE IS CERTAINLY DIFFERENT THAN THE MYTO HAVE JOY IN THE RECESSIVE FORMS OF THE DISEASE BUT WE HAVE A QUITE SOME WORK TO DO YET TO UNDERSTAND HOW BPS 35, HOW AMONG OTHERS HOW THOSE MUTATIONS INFLUENCE THE AUTOPHAGY PROCESS SO THERE'S CLEARLY SOME WORK TO DO THERE ON THE BASIC SCIENCE PERSPECTIVE. >> CAN I FOLLOW-UP THERE WITH ONE QUICK QUESTION? WHAT IS THE STATUS IF THE FIELD IN TERMS OF LARGE SCALE SEQUENCING OF PD PATIENT? IN ALS ARENA, THERE'S CONSORTIA DEVELOPED ATTEMPTING TO SEQUENCE THOUSANDS OF EXOMES OR WHOLE GENOMES IS THERE THIS KIND OF ACTIVITY GOING ON? >> SURE. WE'RE PART OF IT, IT'S LED BY MD SINGLETON WHO IS HERE, PERHAPS WE'LL TALK ABOUT THAT TOMORROW. OR LATER TODAY. I DON'T KNOW WHEN HE'S DISCUSSING BUT SO FAR NOTHING NEW HAS COME, NOTHING NEW HAS COME OUT OF THAT YET. ALTHOUGH OUR EXPERIENCE IN ALZHEIMER'S DISEASE IS YOU NEED TO HAVE SEQUENCED TWO OR THREE THOUSAND BEFORE YOU START TO MAKE MORE FINDINGS. UPDATED GWAS IS HOPE TO COME ABOUT NEW LOCI, SEQUENCING IS NOT REVEALED ANYTHING NEW. IT WILL BUT NOT YET. >> THE ARCLS CONSORTIUM IS THINKING THAT AMIA NEED TO GET POWER ON THE ORDER OF 20,000 EXONLIES. , A LOT OF WORK TO BE DONE. >> EXACTLY. ANALYTICAL WORK IS WHAT TAKES TIME, T IT'S A PAIN IN THE NECK. >> JOHN, I WANT TO ASK YOU A QUESTION. BECAUSE THE GENETICS SAYS GUIDED CELL BIOLOGY ENTIRELY. PEOPLE SAY GENETICS IS A SMALL SUBSET IN SPORADIC WHERE IT'S AT, TO WHAT EXTENT IS THAT TRUE IN TEN YEARS? IS GENETIC COMPONENT MORE COMPLEX THAN CURRENTLY THOUGHT? >> I HAVE NEVER LIKED THE STRICT DIVISION BETWEEN SPORADIC AND GENETIC. I DO THINK, I WAS TALKING TO PEOPLE FROM ART COOKSON'S LAB ANOTHER THE COFFEE BREAK. I NEVER LIKED WHEN I KNOW CELL BIOLOGY GUIDED GENETIC. THAT WAS UNRELIABLE. AND YOU NEEDED A GENETICIST IN CHARGE OF EVERY PROJECT. BUT I AM SLOWLY CHANGING MY MIND THAT THE CELL BIOLOGISTS ARE GETTING BETTER AND THE GENETICS IS GETTING MORE DIFFICULT SO WE ARE STARTING TO SEE OCCASIONS WHEN THE -- CELL BIOLOGY AND BIOINFORMATICS IS POINTING TOWARDS GENE FOR SURE. >> I'LL COMMENT ON MITOCHONDRIA FIRST, MITOCHONDRIA ARE CENTRAL TO ENERGY METABOLISM AND BROAD SPECTRUM METABOLISM IN GENERAL SO AS SOON AS ONE INVOKES PARTICIPATION OF THE MITOCHONDRIA, ONE IS BROADLY INVOKING A VERY COMPLEX SYSTEM, VERY COMPLEX INTERACTION. SO I THINK THAT'S GOING TO BE SOMETHING THAT WILL BE DIFFICULT TO SORT OUT IS THAT INTERACTION THE FOLLOW FOLLOW-UP TO THAT IS POTENTIAL FOR THE NETWORK BIOLOGY, UNDERSTANDING SYSTEMS BIOLOGY IF YOU WILL, THIS IS GOING TO BE SOMETHING THAT'S WELL BEYOND MANY IN THIS GROUP TODAY BECAUSE IT WILL TAKE RETRAINING IN -- TO ENABLE ONE TO THINK IN TERMS OF A NETWORK AS A THERAPEUTIC TARGET. IT'S NO LONGER CONCEPT OF ADAPTABILITY IN COMPLEX SYSTEM NETWORK INTO ACCOUNT THE CONCEPT OF A SINGLE TARGET BECOMING VERY DIFFICULT. SO THAT'S SOMETHING WE WILL NEED TO INVEST IN RE-EDUCATION, RETRAINING, AND RETHINKING A LOT OF APPROACHES IN TERMS OF NETWORK THEORY. >> THIS QUESTION OF NETWORK SCIENCE, ONE PAPER I FEEL IS OVERLOOKED IN THE FIELD IS THE PARKEN TWO MUTATION THAT WHEN THEY COME THROUGH THE GERM LINE THEY SEEM TO INCREASE THE RISK FOR PARKINSON'S. BUT WHEN THEY OCCUR SOMATICALLY THEY'RE CANCER GENES ONCOGENES. P SO EVEN THE SAME AMINO ACID. THE DIFFERENCE IS GERM LINE TRANSMISSION AND MY SUSPICION WE DON'T KNOW BUT I THINK WE COULD LEARN A LOT ABOUT IT, THIS ADAPTATION IS HAPPENING DURING EMBRYONIC DEVELOP. AND FROM THIS AP DAPPATION FINDING IN A NETWORK ONE ROAD IS BLOCKED. IF YOU BUILD UP THE SYSTEM YOU MIGHT MAKE YOURSELF AROUND IT. WHEN YOU ALREADY THE WHOLE CITY IS BUILT AND ROADS ARE THERE AND THEN YOU BLOCK IT IT MIGHT BE MORE DIFFICULT TO FIND CIRCUMVENTING GO AROUND IT. SO I THINK WE CAN LEARN A LOT ABOUT LOOKING AT ADAPTIVE MECHANISMS FROM A NETWORK POINT OF VIEW AND THE WHOLE OF THE GENOMICS, PROTEOMICS, METABALOMICS AND INTEGRATE THOSE DATA AND LOOK AT IT FROM LIKE A MOBILE HOW MANY WAYS DO YOU HAVE -- ARE YOU ABLE TO GET TO BETHESDA. I THINK IS WHERE WE WILL LEARN A LOT ABOUT. AND ITS SYSTEMS APPROACH. I AGREE, WE ARE NOT TRAINED THIS IT. >> FOLLOW-UP ON THAT. SO WHAT DO YOU THINK IS GOING TO BE THE KEY CHALLENGES FOR IMPLEMENTING INFORMATICS GLOBALLY? YOU TALKED ABOUT USING THEMES FROM DIFFERENT KINDS OF DISCIPLINES. BUT WHAT DO YOU SEE THE MAIN ROADBLOCKS TO DECONVOLUTING THESE DIFFERENT EFFECTS? >> BASICALLY THE BIGGEST ON STACKCLE -- OBSTACLE I CONFRONTED IS BIOSTATISTICIANS AND INFORMAT CYSTS IN A DIFFERENT DEPARTMENT. IT SOUNDS SILLY BUT AS SOON AS I BROUGHT BIOINFORMAT CYST IN TO MY GROUP, WE BEGAN TO MAKE PROGRESS. IT WASN'T WE WEREN'T DEALING WITH VERY, VERY COMPETENCE PEOPLE, IT WAS A MATTER THERE WAS TOO MUCH BARRIER JUST BETWEEN THE BIOLOGY AND THE COMPUTATIONAL ASPECT. SO I THINK IT REALLY IS A FULL INTEGRATION OF COMPUTATIONAL BIOLOGY INTO BIOLOGY. AND THAT REALLY TAKES BREAKING DOWN THE TRADITIONAL DEPARTMENTAL STRUCTURE TO ALLOW REALLY TO INTERACT AS WE SHOULD BE IN RESEARCH. >> YOU'RE BIOINFOMATITIONS AND STATUSTITIONS AND PEOPLE TO BRING INTO THE LAB HAS CHANGED OVER TIME. IT'S NOT JUST COLLECTING THE DATA AND PUTTING THEM INTO SOME FORMAT AS WHAT BIOINFORMATICS USED TO BE COLLECT AND PRESENT THE DATA. IT'S NOW LOOKING AT IT OVER TIME AND IN OUR CASE IT WAS THEORETICAL SYNTHESIS, DEALING WITH DYNAMICS, NON-LINEAR DYNAMICS ABLE TO GRASP THOSE COMPLEX COUNTER INTUITIVE INTERACTIONS THAT PEOPLE KNOW FROM PHYSICS AND CHEMISTRY FOR 50 YEARS TO MOVE TO BIOLOGY. IT'S A DIFFERENT KIND OF TRAINING PHYSICS I THINK IS A VERY IMPORTANT BACKGROUND TRAINING FOR THAT. Q. RICHARD. DISCUSS FURTHER POINTS? >> MPTP IS A MITOCHONDRIAL TOXIN. I NEVER UNDERSTOOD MPTP SELECTIVE ATTACK ON TAUPE MEAN NEURONS, I WAS TOLD BECAUSE IT ONLY WENT TO DOPAMINE NEURONS BUT THAT SEEMS BOGUS TO ME NOW. >> I THINK YOU'RE RIGHT. I THINK IT IS BOGUS. IT KILLS THOSE NEURONS BUT I DON'T THINK It GIVES INSIGHT TO THE PATHOPHYSIOLOGY OF PD BECAUSE IT HAPPENS TO BE MITOCHONDRIAL TOXIN. I DON'T THINK IT MATTERS WHAT YOU HIT IT'S TAKEN UP BY THE DOPAMINE AKNEE MOW TRANSPORTER. SELECTIVELY TAKEN BY THE TAUPE MEAN TRANSPORTER SO ONLY IN THOSE CELLS, VERY HIGHLY ENRICHED IN THOSE CELLS. WOULDN'T MATTER WHAT YOU DID. THE REASON IT'S SELECTIVE IS BECAUSE OF THAT. NOT BECAUSE ANYTHING TO DO WITH MITOCHONDRIA. THE BETTER MODE IS MODEL, THAT'S A MITOCHONDRIAL TOXIN. (OFF MIC) >> ONE MORE QUESTION ON MITOCHONDRIA. THERE'S EVIDENCE FOR CONNECTIVITY IN OTHER KINDS OF NEURODEGENERATIVE DISEASES WITH MITOCHONDRIA. HOW WE MIGHT LEARN THINGS FROM OTHER NEURODEGENERATIVE DISEASES CONNECTED IN SOME WAY WITH MITOCHONDRIA. >> THERE IS A LOT OF INTERESTING MEDICINE IN PEOPLE THAT HAVE MUTATIONS IN MITOCHONDRIAL DNA BECAUSE WE KNOW WHAT'S GOING ON THERE. THEY PRESENT WITH A WIDE RANGE OF PHENOTYPES, VERY COMPLY CATTED JUST LIKE YOU WERE SAYING. SOME PATIENTS TWO PATIENT CONSIST HAVE THE SAME MUTATION IN MITOCHONDRIAL DNA BUT DIFFERENCE LOAD CAUSES DIFFER DISEASE SO NOT JUST HIGHER MUTATION LOAD CAUSES THIS PLUS MORE, YOU CAN ACTUALLY SKIP THE DISEASE AND GET DISEASE 2 WITH GREATER LOAD AND THEN TO YOUR POINT YOU START OUT YOUNG IT IS EXTREMELY COMPLICATEDDED. FOR WHAT I'M INTRIGUED BY, WE TALK ABOUT IPS CELLS AND WHAT A GREAT MODEL, THERE'S A FASCINATING PAPER BY (INDISCERNIBLE) FROM HELSINKI, SHE TOOK CELLS, SKIN CELLS FROM PATIENTS THAT HAD MITOCHONDRIAL DNA MUTATIONS. WE ALL BECOME HETERO PLASTIC WITH TIME BECAUSE WE'RE ACCUMULATING MUTATIONS. SAY THEY'RE 50/50. TYPICALLY IN THOSE CELLS THEY MAINTAIN THAT SAME HETERO PLASMIC LOAD THROUGH TIME AND CULTURE BUT WHEN SHE DEDIFFERENTIATED TO IPS CELLS THEY SEGREGATED IN SOME CELLS WERE ALMOST ALL MUTANT OTHER IPS CELLS WERE ALL WILD TYPE AND SIMILAR TO WHAT HAPPENS IN THE FEMALE GERM LINE, INTERESTING THAT WHEN YOU THINK ABOUT IPS CELLS FOR CERTAIN DISEASES COMPLICATED THAN YOU THINK. MITOCHONDRIA ARE ALIVE BY ENDOSYMBIOSIS. AND WHEN YOU LOOK AT (INAUDIBLE) VIRUS INFECTION IN THE HEART, WHERE YOU HAVE MITOCHONDRIAL DAMAGE, WHAT SEEMS TO DO THE DAMAGE IS RELEASE OF MITOCHONDRIAL DNA WHICH IS RECOGNIZED APPARENTLY AS BACTERIAL DNA AND TRIES THEN TLR 7 AND 9 WHICH IS A MIMICRY OF BACTERIAL RESPONSE, AND I JUST WONDER WHETHER IN MITOCHONDRIAL DEFICIENCIES WHEN POTENTIAL MITOCHONDRIAL POTENTIAL IS OVER DEPOLARIZING YOU GET DNA OUT OF IT AND IT'S OVERLAID WITH INFLAMMATION WHICH IS DIFFERENT FROM ENERGY DEFICIENCY. SO WE ARE DEALING WITH INFLAMMATION RESPIRATORY DEFICIENCY, AND THEN LOOK AT ALL PD MOLECULES, ALMOST ALL PD GENES, SEEM TO HAVE INFLAMMATORY OR IMMUNOLOGICAL ROLES AT THE SAME TIME. MAYBE SOMETHING GOOD INFLAMMATION, WHO KNOWS. WHAT TWO FUNCTIONS IN ONE MOLECULE AND THIS WILL BE VERY DIFFICULT TO DISECT. >> SO THERE WERE TWO PEOPLE STANDING UP PRESUMABLY TO ASK QUESTIONS. WE HAVE ONE MINUTE. DO YOU WANT TO ASK YOU QUESTION? >> SO MY NAME IS (INAUDIBLE) FROM UNIVERSITY OF ALABAMA BIRMINGHAM. AND WHEN WE'RE LOOK AT PATHWAYS ASSOCIATED WITH PATHOGENESIS OF PARKINSON'S DISEASE, WE HAVE BEEN TALKING ABOUT ALPHA SYNUCLEIN. IT IS IMPORTANT TO DEFINE THE SPECIES WE'RE LOOKING AT AND THERE'S 100 YEARS OF RESEARCH DEFINING THE CHARACTERISTICS OF LEWI BODIES AND THAT THEY ARE FILL MEANTOUS. THEY'RE INSOLUBLE. THEY'RE PHOSPHORYLATED THEY'RE UBIQUITINATED AND COMPOSED OF ALPHA SYNUCLEIN. SO LOOKING AT GENETIC MODIFIERS OF ALPHA SYNUCLEIN AND THAT WE RECAPITULATE WHAT'S GOING ON IN DISEASE BRAIN. >> GOOD POINT. MANY MODEL SYSTEMS THAT ARE USED ARE NOT NECESSARILY FULFILLING ALL THOSE CRITERIA. I GUESS THE QUESTION IS, IF YOU YOU ULTIMATELY IDENTIFY A DRUG TO BYPASS THAT, DOES THE STATE MATTER IF IT'S BIPASSED OR -- BY PASSED OR EXAMPLE IN AUTOPHAGOSOMAL CARE IT'S DIFFERENTIATED SO THERE MIGHT BE DIFFERENT WAYS TO THINK ABOUT IT AS WELL IN TERMS OF MODIFICATION OR FORM IT'S IN. ANYBODY ELSE HAVE COMMENTS ON THAT? >> I THINK WE'RE EXACTLY AT THE RIGHT TIME. SO WE'LL STOP. >> STAY WHERE YOU ARE. >> DMITRI, IS DMITRI ON THE LINE? >> CAN I ASK MY QUESTION NOW WITH EVERYBODY SITTING DOWN ON THE PANEL? >> BEFORE YOU DO THAT, THIS IS THE LAST 30 MINUTES OR SO OF THIS SESSION AND THE INTENTION IS TO DISCUSS THE OVERALL PRIORITIZATION OF THE RECOMMENDATIONS WHICH YOU PROBABLY GUESS FROM THE GROUP OF US WE BROADLY AGREED TO THE RANKING OF THE RECOMMENDATIONS AS WE PICK THEM, THAT'S WHY WE THOUGHT IT WOULD BE APPROPRIATE AND CERTAIN HLY KEEN TO HEAR QUESTIONS FROM THE AUDIENCE, WE ALSO HAVE QUESTIONS THAT HAVE COME IN THROUGH EMAIL AND WE'LL GET TO THOSE AS WELL. BUT I THINK SINCE VIRGINIA IS READY TO GO STRAIGHT TO ASK VIRGINIA ROLLING GO TO THE PAM BECAUSE YOU HAVE HEARD QUITE BIT FROM US ALREADY. >> I THINK WE TALKED ABOUT MODELS. I WANT TO HEAR YOUR OPINION AND -- ON USING MODEL SYSTEMS THAT TO STUDY NETWORK AND CIRCUITS AND PATHWAYS, WHERE THE PROTEIN SNOT EXPRESSED IN THAT ORGANIZE ITCH, NIGH, WORM, YEAST, THEY DON'T EXPRESS ALPHA SYNUCLEIN, SO IF YOU OVEREXPRESS A LOT OF PROTEIN, THE ORGANISM DOESN'T MAKE THAT PROTEIN SO VALID MODELS TO STUDY THE BIOLOGY OF ALPHA SYNUCLEIN OR PATHOBIOLOGY OF ALPHA SYNUCLEIN. THAT'S MY FIRST QUESTION, SECOND IS BACK TO WHAT LAW ARE BOCELLI SAID. SO THERE'S TOXICITY. THERE'S FORMATION THAT COULD LEAD TO TOXICITY. THOSE TWO ARE THE SAME THING OR ARE THEY DIFFERENCE THINGS? IF YOU OVEREXPRESS A LOT OF PROTEIN TO MANIPULATE THE PATHWAY THE CELL DRIES SO ARE YOU MODELING -- DIES. SO YOU MODELING PARKINSON'S DISEASE? WHAT ARE ARE YOUR THOUGHT ON THESE TWO QUESTIONS? >> YOU BROUGHT UP THE MODEL ORGANISM RECENTLY. >> THE MAIN RATIONALE FOR THE MODEL ORGANISM EXPERIMENT COMES FROM THE FACT THAT THAT'S WITH THE EXCEPTION OF AUTOPHAGY ENHANCERS THAT'S THE ONLY EXAMPLES OUT THERE FOR FINDING A DRUG BASED ON SCREENING TECHNOLOGY THAT I KNOW ABOUT. OTHER EXAMPLES, FEEL FREE TO DISCUSS THEM. CLEARLY THERE'S LIMITATIONS TO VARIOUS MODEL SYSTEMS. MY PERSONAL VIEW IS -- WOULD BE PROBABLY WAY BETTER TO DO THIS IN NEURONAL CELL LINE IPS CELL LINE WHERE YOU CAN LOOK IN DETAIL AT RELEVANT SPECIES. IN PRINCIPLE HAVE THE WHATEVER MUTATION ENCODED AND NOT TRANSIENT OR INDUCED OVEREXPRESSION. GENETICALLY ENCODED ON THE CHROMOSOME. BUT-ONE RECENT EXAMPLE A DRUG IDENTIFIED, POTENTIALLY ACTIVATING DOWNSTREAM OF THE PATHWAY ALL TOGETHER. SO SORT OF A BYPASS MECHANISM POTENTIALLY IN SOME WAYS. YOU CAN REPLY. >> SO I THINK IT'S REALLY IMPORTANT, TO REITERATE WHAT I MENTION BEFORE, WHICH IS THAT I THINK WE HAVE TO FOCUS ON STUDYING WHAT IS RATHER THAN WHAT IS POSSIBLE. I AGREE OVEREXPRESSION IN A MODEL SYSTEM IS A HUGE COMPOUND AND THAT I THINK WHAT'S REALLY IMPORTANT ONLY CHECK WE HAVE IS WE HAVE TO TRY OUR BEST TO TRY TO CONNECT WHAT WE SEE IN MODEL SYSTEM, WHAT HAPPENS IN HUMAN DISEASE. THAT'S WHY FOR EXAMPLE HAVING THE PATIENT TISSUE POSTMORTEM TISSUE IS, THOUGH IT IS IMPERFECT FOR LOOKING AT MECHANISMS, IT IS CRUCIAL BECAUSE IT PROVIDES US WINDOW AND ALLOWS US TO CORRELATE WHAT'S HAPPENING IN OUR ANIMAL MODEL -- MODEL SYSTEM WITH THE DISEASE. >> I HAVE NO PROBLEM WITH OVEREXPRESSION EXCEPT THAT IF YOU OVEREXPRESS A PROTEIN IN THE FLY FOR EXAMPLE, THEY'LL USUALLY MAKE THE PROTEIN. AND YOU MAKE REALLY KIND OF BOLD STATEMENT BASED ON THOSE TYPE OF SYSTEMS ALL -- I'M NOT SAYING IT'S BAD, I'M SAYING WHAT DO YOU THINK? JOHN, YOU'RE IN A O -- COMPANY, WOULD YOU BASE ON THAT DATA OF FLY MODEL OVEREXPRESSION OF SYNUCLEIN AND SOME COMPOUND RESCUE TOXICITY THAT YOU GO TO CLINICAL TRIAL WITH THAT INFORMATION. THIS IS ALL I'M SAYING, THAT YOU GENERATE INFORMATIONAL PATHWAYS. BASED ON THE FLY OR WORM OVEREXPRESSING ALPHA SYNUCLEIN. AND GO DEVELOP A DRUG AND -- BASED ON THAT. I'M JUST TRYING TO UNDERSTAND YOUR -- ALSO WHAT WE'RE TRYING TO MODEL. >> I JUST SAY ONE THING VIRGINIA BEFORE JOHN PUNCHES IN. WE WORK WITH FIVE OFFER SIX GROUPS THAT FOUND MODIFIERS IN FLY, YEAST, AS YOU DESCRIBE. WE WERE SKEPTICAL AT FIRST BUT PUT THEM INTO THE PRIMARY NEURON OR IPS MODEL. I SAY TWO-THIRDS OF THE TIME THEY HAVE MODIFYING ACTIVITY IN THOSE MODELS. >> WHAT ABOUT THE MOUSE? >> TWO HAVE GONE ALL THE WAY TO THE MOUSE AND HAD DRAMATIC EFFECTS. THOSE COVER PD A HEALTHCARES, STD SO IT'S NOT DISEASE SPECIFIC SO I THINK MODEL VERSUS A ROLE TO PLAY, THEY'RE CHEAP, FAST, SO I'MNA FAVOR OF THEIR USE. STEVE ANSWERED THE QUESTION NICELY ARTICULATING THAT. I DON'T THINK ANYBODY HAS GREAt DEAL OF CONFIDENT TO ADVANCE MOLECULES SOLELY ON THE BASIS OF DATA COMING OUT OF A FLY MODEL BUT IF YOU HAVE DOWNSTREAM VALUE ATION INTEGRATED APPROACH. THE OVEREXPRESSION IS ALSO A VALID WAY TO GO BECAUSE IT CAN POTENTIALLY AMPLIFY EFFECTS THAT ARE HARD TO SEE INITIALLY AND YOU CAN FIGURE OUT HOW TO MODEL THOSE BETTER TO RELEVANT MODEL SYSTEMS. SO OuR EXPERIENCE SNOT AS >> WHAT ABOUT OVEREXPRESSION OF TOXICITY, AS A MODEL FOR PD? >> DON'T EXPRESSION RELEVANT PROTEIN AND LIKE TAU SYNUCLEIN YOU OVEREXPRESSION. AND YOUœHAVE PATHWAYS AN CAN YOU GUYS ANSWER THAT QUESTION. MY SECOND QUESTION, TOXICITY MERELY MODEL PD OVEREXPRESSING LOCK 2 OR ALPHA SYNUCLEIN AND CREATE TOXICITY AND THEN YOU RESCUE THAT TOXICITY, WOULD YOU TAKE IT TO CLINICAL TRIAL? >> I DON'T THINK YOU WOULD TAKE THAT TO THE BANK, YOU'RE PUSHING ME HARD IN tHIS BUT GONE ARE DAYS WE'RE EXCITED ABOUT THAT RESULT IN ISOLATION AND CHARGE TOWARDS THE CLINIC AND HOPE WE HAD SOMETHING THAT IS A MIRACuLOUs CUrE. ALLœHAVE MODEL LIMITATIONS ONE THING THAT'S COME OUT ACROSS THE DISCUSSION WITH THE SPEAKERS IS THAt ANIMAL MODELS PLAY A KEY ROLE, IPS CELLS PLAY A KEY ROLE BUT THEY HAVE THEIR OWN UNIQUE LIMITATION WHICH IS MEANS YOU CAN USE ONE AT EXPENSE OF EXCLUDING ANOTHER. >> DID YOU YOU NEED TO CAPITALIZE ON THE COMMUNITY AS A WHOLE TO BE COMPLIMENTARY OF WHAT WE DO, NONE OF US HAS THE TIME OR RESOURCES TO IN YOUR OWN LAB TO HAVE YEAST FLY FISH MICE AND PATIENTS. CHEMICAL BIOLOGY AND SYSTEMS BIOLOGY AND ALL THAT. WHEN WE LOOK AT THE PROBLEM WE REALIZE WE NEED TO FIND SOME HOLISTICS TO GET TOXICITY SO I LIKE THESE IN YEAST, THE SIMPLE ONE EUKARYOTIC BUT NOT NEGLECT CELL CELL INTERACTIONS, IT'S LARGELY OVERESTIMATED AS THE SOLE OF THE BRAIN. HOW THEY CROSS TALK AND TALK TO EACH OTHER. THIS IS VERY DIFFICULT TO MODEL IN IpS THOUGH WE WILL HAVE POTENTIAL TO MAKE CO-CULTURES AND TRIPLE CULTURES AND P SO ON TO MAKE ORGAN SYSTEM SPACE SO MORE TO START QUICKLY MOVE ON, GO BACK AND I THINK IN THE COMMUNITY, IF INTERACTION WILL BE SUPPORTED BY NIH OR FUNDING AGENCYIES, HOWœYOU CAN MAKE A CASE FOR ON SOURCE YUM BASED QUICK STRATEGY WE GET THE MOST FOR OUR MANIPLE >> QUESTION ON THE FRONT THEN TO THE BACK. >> VERY USEFUL IMPORTANT TO MAKE SURE THEY ACTUALLY REPRODUCE THE PROCESS WE'RE TRYING TO STUDY. ONE EXAMPLE IS THE YEAST MODEL I HAVE SERE OVER AN OVER USED AS MODEL OF AGGREGATION. WHAT YOU SEE IN YEAST IS AGGREGATE, RATHER VESICAL ACCUMULATION OF ALPHA SYNUCLEIN. SO THERE MAYBE USEFUL IN TELLING US THINGS ON THE PATHWAY THAT SYNUCLEIN AXON BUT NOT USEFUL IN TRYING AS AGGREGATION MODEL OR TRYING TO CORRELATE AGGREGATION WITH THE PHENOTYPE. >> ANYONE COMMENT ON THAT? >> IT'S IMPORTANT SUSAN JUMPED TO IPS CELLS AND THEY ARE BACK TO BACK PAPERS. THAT IS WHERE THE ADVANTAGE WAS, IN YEAST STUDY ALONE IT WOULDN'T HAVE BEEN AS CONVINCING. >> QUESTION PLEASE THANK YOU. >> LISA SHULMAN UNIVERSITY OF MARYLAND. THIS MORNING IN THE SESSION AND THIS AFTERNOON WE HAVE BEEN TALKING ABOUT INTEGRATED PD DATABASES WHICH IS NUMBER 4 RECOMMENDATION. ONE OF THE THINGS THAT IS CONCERNING WHAT IS THE MECHANISM FOR FUNDING A DATABASE WHICH IF YOU'RE GOING TO PUT IN THE EFFORT TO DO THIS, NOT ONLY IS VERY COMPLEX REQUIRE MAINTENANCE STARTUP, MAINTENANCE, BUT THE PURPOSE TO HAVE LONG TERM FUNDING SO YOU CAN CONTINUE TO ADD TO IT. I WONDER IF THERE IS, MAYBE NIH FUNNING COME FROM FOR THIS KIND OF A VERY LONG TERM STRATEGY. >> MONICA, DO YOU WANT TO MAKE A COMMENT? THOUGH INVESTIGATORS IN THE AUDIENCE KNOW RO-1 AND GRANT MECHANISMS THERE'S OTHER MECHANISMS TO LOOK AT BUILDING DATABASES, THAT HAVE TO BE LONGER TERM AND MORE STABILITY. SO WE HAVE WITHIN AND ACROSS NIH MECHANISMS THAT OTHER INSTITUTES USE THAT WE OTHER LOOKING AT NOW TO BUILD DATABASES LIKE THAT. SO WE WANT TO LEARN FROM NHLBI OR NC, NHGRI IN TERMS OF APPROACHES FOR GENOMIC DATABASES THAT ARE THERE AND SEE IF WE CAN LEARN FROM THEM AND WHICH WOULD ON THAT. >> THANK YOU. >> CAN I MAKE A COMMENT? I MENTION THAT THE NACK OF REPOSITORY FOR ALZHEIMER'S DATA AS WE AS PARKINSON'S TO LOOK AT BUT SEVERAL CENTERS ARE NOT REQUIRED AS FOR ALZHEIMERS SEVERAL UDALL ISN'TERS THAT HAVE CLINICAL COHORTS FOLLOWED LONGITUDINALLY. I KNOW TOM MONTINE'S DATABASE IS TERRIFIC. WE COLLABORATED TOGETHER. OUR TEAM WOULD WITHOUT HIATION MAKE OUR DATABASE AVAILABLE FREELY TO WHOEVER WANTS TO PAY FOR IT TO INTEGRATE WITH TOM. ALL THE HEAVY LIFTING IS DONE. THE PHENOTYPING IS DONE. THE INEXPENSIVE HE WAS TO INTEGRATE AND HOPEFULLY WILL BE ALIVE. WE DON'T KNOW BUT HOPE TO CONTINUE TO ADEQUATE TO THAT. I WOULD -- WE HAVE TAKEN -- WE HAVE AN INTEGRATED DATABASE FOR ALZHEIMER EASE PARKINSON, ALS AND FTD AND WE HAVE A GRANT WITH J AN J ALL THE 10,000 PATIENTS IN THAT DATABASE WITH 1500 AUTOPSIES. PUBLISHING STUDIES. I WOULD LOVE TO MAKE THAT AVAILABLE TO PEOPLE, CERTAINLY TOM WOULD TOO. IT WOULD BE PENNIES TO A FEW DOLLARS. I DON'T KNOW IF TOM WANTS TO WEIGH IN BUT I LOVE PEOPLE TO HAVE ACCESS TO THE DATA IN WAYS INEXPENSIVE AND USEFUL, WE'RE NEIGHBORING USE OF IT. IT IS AN OPEN INVITATION FROM PENN UDALL CENTER. >> CERTAINLY VOLUNTEERING JOHN TO TAKE RECOMMENDATIONS TO THE NEXT STEP. REITERATE THIS WAS ONE OF THE RECOMMENDATIONS THAT GOES BROADLY ACROSS BASIC TRANSLATIONAL AND CLINICAL GROUP AND WE'LL TALK ABOUT THAT TOMORROW. AS WE WRAP UP THIS SESSION. YOU HAD A COMMENT THEN TED. >> MAYBE A PUT A EUROPEAN PERSPECTIVE ON THE ISSUE OF DATABASES AND INFRASTRUCTURE, ABOUT TEN YEARS, 15 YEARS AGO THERE WAS A HUGE DISCUSSION IN EUROPE ABOUT BIOLOGY AND BIOMEDICINE, NEED INFRASTRUCTURE AND IT WAS DOMINATED BY THE PHYSICS COMMUNITY, WHO ARGUED WE NEED TO FIND EXPOSEON AND NEED A COUPLE OF BILLION DOLLAR INVESTMENTS INTO MAKING THIS INFRASTRUCTURE FOR THE ENTIRE IMMUNITY THAT LED TO THE EUROPEAN STRUCTURE FORM INFRASTRUCTURE FOR RESEARCH AND NOW THERE ARE ABOUT TEN OR SO LONG TERM FUNDED INFRASTRUCTURE COMPONENTS IN THE EUROPEAN OTHERWISE 2020 AND 7 FRAMEWORK. ONE IS E LICKSIA WHICH IS BIOINFORMATICS INFRASTRUCTURE. ANOTHER IS THE BIOBANKING INITIATIVE ALL OVER EUROPE. IN TERMS OF DATABASES THEY SHOULD BE PART OF THE BIOBANK BECAUSE THEY SHOULD BE HIGHLY COUPLED TO THE INDIVIDUAL PATIENT SAMPLE, BIOSAMPLE, BASICALLY A DESCRIPTOR OF PATIENT SAMPLE. SO THAT IS WHERE WE NEED OF COURSE TO LOOK FOR FUNDING, IT CANNOT BE PROJECT FUNDED WHICH WAS THE CASE IN EUROPE 10, 15 YEARS AGO. SO EACH WROTE APPLICATION IN THE STRUCTURE APPLICATION AND AFTER THREE YEARS IT WAS PULLED NOT BECAUSE IT WAS BADLY DONE BUT BECAUSE FUNDERS BECAME INPATIENT AND IT HAD A DIFFERENT REASON. IN TERMS OF THE MECHANISMS TO KEEP THE DATABASES UP TO DATE, WHICH IS THE BIGGEST ISSUE WE NEED TO MOVE OVER TO ACCOUNT SOURCING MODEL BE IT, WIKIPEDIA HAS LOTS OF PROBLEMS, BUT IT IS ONE WAY, HAVE THOUSANDS OF PEOPLE GLOBALLY LOOK AT IT AND MAYBE HAVE NIH, MICHAEL J. FOX EUROPEAN INSTITUTIONS TAKE OVER THE ROLE AS MENTOR TO MAKE SURE IT'S NON-PROFIT OR WHATEVER, IT CONVERGES FOR THE COMMUNITY. THAT'S WHERE THE FUTURE IS AND THE DISEASE PATIENT ORGANIZATION I THINK CAN PLAY A BIG ROLE IN HERE TO BE THE CURATOR OF THAT THIS KNOWLEDGE IS ASSEMBLED, PUT IN AN INFRASTRUCTURE, MADE AVAILABLE TO A REASONABLE COST PRICE, SO ON. >> >> I BELIEVE THAT THAT'S TRUE BUT I THINK IT'S ACTUALLY ONLY AN INTERIM SOLUTION BECAUSE AS SOON AS RESOURCES DEVELOP TO THE POINT THEY CAN BE USED IN DIAGNOSIS AND DISEASE MANAGEMENT, THE ENTIRE HEALTHCARE SYSTEM TAKES OVER, THAT IS WHERE IT IS SERVING IN THE LONG RUN BUT JUST INTERIM TO GET THERE. >> SO THAT'S GOO AS WELL. THE OUTCOME IS GOOD THEN. >> MAYBE SOME THINGS WE CAN LEARN TRILLION EUROPEAN INITIATIVES ON THE GOD SIDE AND CLINICAL HECKING SIDE. LET'S TWO TO TED WAITING PATIENTLY. >> TED (INAUDIBLE) JOHNS HOPKINS. I WANT TO BRING UP READDRESS SOMETHING BROUGHT UP EARLIER ABOUT TRANSPLANTATION. AT LEAST IN MY MIND, IF YOU LOOK AT DATA THERE'S SUBGROUPS OF PATIENTS WHICH BENEFIT TREMENDOUSLY AND HAVE SUSTAINED BENEFIT FROM TRANSPLANTATION. WITH ADVANCE IN ABILITY TO MAKE GMP QUALITY DOPAMINE NEURONS FROM ES OR IPS CELLS, THERE SHOULD BE A STRATIFICATION METHOD OR DESIGN WHICH SUBGROUPS OF PATIENTS CAN BE IDENTIFIED THAT WOULD BENEFIT FROM TRANSPLANTATION. IN PARTICULAR THE AUTOSOMAL RECESSION PD WOULD BE BENEFICIAL TO THAT. I WAS SURPRISED THAT WASN'T ON YOUR LIST STUDY INVESTED IN. >> ANOTHER COMMENT. I DID COMMENT THAT EARLIER. SO THERE IS A FUNDED PROJECT IN NEW YORK TRYING TO GET THROUGH HUDDLES OF USING IPS CELLS, HE'S USING EMBRYONIC STEM CELLS FOR DOPAMINE NEURONS AND IN TO THELY IN THIS CASE FOR PARKINSON'S DISEASE, THAT IS UNDERWAY. I MENTION BRIEFLY THE BIG EFFORT FROM ROGER BAR IN EUROPE TO DO I THINK A LARGE PATIENT TRIAL WITH FETAL TISSUE BUT STRATIFYING THE PATIENTS BETTER TAKE INTO ACCOUNT BUT IT'S PUT ON THE TABLE AND DISCUSSED. IT FALLS WITHIN IPS CELLS AND P GENERATE DOPAMINE NEURONS FROM THEM THEY WILL BECOME USEFUL IN THOSE TYPES OF TRIALS. THE OTHER THING IPS CELLS YOU CAN ENGINEER CELLS TO IF YOU GET DYSKINESIA WITH 25% PATIENT DYSKINESIA, YOU CAN THEN EFFECTIVELY KILL THE CELLS OFF IF YOU HAD -- THAT RATE IS REGULATORY ISSUES BUT MORE PLASTIC AND ADAPTABLE IN FETAL TISSUE. I'M WILLING TO DISCUSS IT IN FRONT OF PEOPLE, END TO ONE OF THOSE RECOMMENDATIONS, FURTHER DOWN BUT AN INTERESTING IDEA. >> MORE QUESTIONS BEFORE WE WRAP UP. >> UNDERSTAND BROOK MEDICAL UNIVERSITY. AS TECHNICIAN I WANT TO MAKE A COMMENT MORE GENERIC COMMENT ON THE RECOMMENDATIONS SUCH THAT TWO THAT WERE IMPORTANT IN THIS AFTERNOON DISCUSSION OPT LIST NUMBER 3 AND 6 ABOUT THE TRANSLATIONAL RESOURCES THAT WOULD GIVE BETTER PREDICTION FOR CLINICAL EFFICACY. IN RECOMMENDATION NUMBER 6, WHAT WE HEARD IS NOT SO MUCH APPLICABLE TO OTHER AREAS OF CLINICAL TREATMENT NEEDS, SYMPTOMATIC THERAPIES. NOT IS MUCH APPLICABLE OF WHAT YOU DO TO IMPROVE CLINICAL TRIALS DESIGN OR CLINICAL TRIAL SUCCESS IN PROBLEMS LIKE SAY ORTHO STATIC HYPERTENSION URINARY INCONTINENCE AND QUALITY OF LIFE IMPACTING PROBLEMS IN PARKINSON'S DISEASE. SO THIS COMMENT IS MEANT TO SAY WHEN THESE RECOMMENDATIONS ARE FINALLY GROUPED AND SHAPED AND BRIDGED ACROSS THE GIVEN GROUP, CLINICAL TRANSLATIONAL BASIC AND ONE SHOULD MAKE CLEAR ONE IS TARGETING THE AREA OF DISEASE MECHANISM AND DISEASE MODIFICATION. >> THANKS FOR THAT COMMENT. WE RECOGNIZE THAT IN OUR GROUP AS WE GOT FURTHER INTO DISCUSSIONS WE FELT WE WERE A LITTLE BIT TOO DISEASE MODIFYING CENTRIC AND WE HAD TO STEP BACK AND LOOK MORE BROADLY, OBVIOUSLY ABOUT IMPORTANT ASPECTS OF THE DISEASE. SO ON. ANOTHER QUESTION, COMMENT? >> PETER SMITH, NATIONAL PARKINSON FOUNDATION. IN THE OCTOBER FROM SWEDEN PUBLISHED ARTICLE NEW ENGLAND JOURNAL OF MEDICINE USING A CLINICAL REGISTRY AS THE FOUNDATION FOR INTERVENTIONAL TRIAL IN CARDIOVASCULAR DISEASE, IT WAS PUBLISHED WITH EDITORIAL SAYING THIS WAS A DATE RUNTIVE INNOVATION IN CLINICAL TRIALS. TO TALK ABOUT IT THERE BEING A SEPARATION BETWEEN A RESEARCH DATABASE AND A CLINICAL DATABASE, THERE'S NOT A CLEAR SEPARATION THERE. THE NATIONAL PARKINSON'S FOUNDATION HAVE YOU BEENING A CLINICAL DATABASE, PARKINSON'S OUTCOMES PROJECT, IT HAS 7500 PROJECTS FOLLOWED LONGITUDINALLY IN 2009. I INVITE ANYBODY WHO WANTS TO ADD ON TO THAT STUDY, IT CAN ADD ON THEIR OWN DATA AND WE FOLLOW WE PROVIDE FUNDING FOR THE FOLLOW-UP AND OUR PLAN IS TO -- IT WAS MENTIONED EARLIER THERE SHOULD BE A REGISTRY FOLLOWING PATIENTS TO DEPTH AND WE ARE FOLLOWING PATIENTS TO DEATH WITH A FAIRLY COMPREHENSIVE SIMPLE DATA SET. SO THERE ARE OPPORTUNITIES OUT THERE, MAYBE NOT ON EVERYONE'S RADAR. >> THANK YOU FOR THAT. TOOLS AND P RESOURCES THAT MIGHT PROVIDE A GOOD PLATFORM TO JUMP OFF TOWARDS THIS GOAL. WE HAVE A FEW MINUTES LEFT. I DON'T KNOW IF WE'RE PLANNING TO TAKE ANY QUESTIONS OR COMMENTS THAT HAVE COME IN. ONLINE. OR ANY OTHER QUESTIONS OR COMMENTS FROM THE AUDIENCE >> I THINK WADE MENTIONED BEFORE SOME OF THE INTEREST IN NEW TECHNOLOGIES THAT'S OBVIOUSLY VERY IMPORTANT. I WAS WONDERING, IS THERE ANY MECHANISM NIH LEVEL THAT BRIDGES TECHNOLOGY DEVELOPMENT WITH NEUROSCIENCE OR PARTICULAR WHAT WE'RE DISCUSSING TODAY. IF WE JOIN PROGRAMS, OBAMA INITIATIVE IS MENTIONED BUT ASIDE FROM THE BRAIN INITIATIVE WHAT ARE THE OTHER MECHANISMS THAT FOR EXAMPLE LINK NEUROSCIENCE WITH >> HISTORICALLY PROJECTS THAT ARE DEVELOPMENT OF TECHNOLOGY COME THROUGH IN SEVERAL MECHANISMS, THE MOST GERMANE IS BIOENGINEERING RESEARCH PARTNERSHIPS SPECIFICALLY FOR LESS HYPOTHESIS DRIVEN BASIC SCIENCE STUDIES AND MORE FOR STANDARD ENGINEERING DEVELOPMENT CREATED TO SPECIFICALLY FIND OUT WHAT ARE THE KEY QUESTIONS THAT NEUROSCIENTISTS CAN'T ANSWER AND TO WORK WITH THE NEUROSCIENTISTS TO DEVELOP THESE TOOLS AND MORE STANDARD ENGINEERING DESIGN FASHION, DESIGN CRITERIA BASED OFF NEEDS AND CREATE A TOOL WITH THE NEUROSCIENTIST AND IDEALLY DISSYSTEMNATE IT OUT TO THE COMMUNITY TO ANSWER SOME OF THESE LINGERING QUESTIONS. >> SERIES OF RFAs ON SINGLE CELL ANALYSIS, AS AN ISSUE THAT CURRENTLY TECHNOLOGIES ARE REALLY POPULATION BASED UNDERSTANDING SINGLE CELL LEVEL HETEROGENEITY SO THAT'S BILLING ONE INITIATIVE. ONE LAST FINAL QUESTION HERE >> BRANDON HARVEY NIDA. MANY STRATEGIES THAT YOU DISCUSS HERE BASED ON SMALL MOLECULE EFFORTS MECHANISMS ARE IDENTIFIED GENE BASED THERAPEUTICS ARE GOING TO ALSO BE VERY IMPORTANT OBVIOUSLY THEY'RE IN THEIR INFANCY NOW WITH THE ADC AND SO FORTH. THOSE ARE ALSO DIRECTED TOWARDS DELIVERY IN HUMANS AND NOT DOPAMINERGIC NEURONS THEMSELVES. I WAS WONDERING IF THE PANEL DISCUSSED EFFORT AND HOW TO GET GENES TO A LITTLE RELUCTANT TO TARGET THAT AREA. WHAT EFFORTS ORER ULTIMATELY IDENTIFYING SOMETHING TO COMBAT MITOCHONDRIAL DYSFUNCTION SO FORTH REQUIRED WITHIN THE DOPAMINERGIC NEURON AND NOT NECESSARILY FROM AN OUTSIDE PERSPECTIVE. THANKS. >> GREAT QUESTION. DOES ANYBODY WANT TO TRY AND -- NOT SURE IT'S SOMETHING WE ACTUALLY GAVE ENOUGH DISCUSSION TO BUT IT'S A VERY IMPORTANT POINT. IT WASN'T WE WERE INTENDING TO BE MOLECULE CENTRIC. WE TALKED ABOUT ALPHA SYNUCLEIN SO WE DIDN'T LIMIT OURSELVES TO SMALL MOLECULES BUT I DON't THINK WE TOUCHED TO ANY GREAT EXTENT ON THAT. STEVE, DO YOU WANT TO COMMENT? >> THERE ARE GROUPS THAT MADE BIG COMMITMENTS TO ANTI-SENSE OLIGONUCLEOTIDE TREATMENTS FOR CNS, THERE'S PROMISING DATA OUT THERE TO SUGGEST THAT YOU CAN DELIVER THOSE IN A WAY THAT GETS TO THE TARGET IT SHALL SHOE. CLIVE HAD EXPERIENCE AS WELL WITH ISYS. >> WE DID ON THE FMA IT WAS MENTIONED BRIEFLY TODAY KNOCKING DOWN THOSE GENES. MIGHT BE INTERESTING WITH SYNUCLEIN FOR HIPPOCAMPAL FUNCTION YOU WORRY KNOCKING IT DOWN WILL HAVE OTHER EFFECTS. THE GENE THERAPY SIDE, JUST FINISHED A BIG TRIAL ON -- WHICH UNFORTUNATELY FAILED. SHUTTING TOWN. THERE'S A NEW TRIAL AT NIH WITH GDNF, AAB APPROACH, LED BY CHRIS BAINITES AND OTHERS. ONLY ONE OR TWO PATIENTS. SO I THINK THAT FIELD IS MOVING FORWARD SLOWLY AFTER THE SET BACK ON THE PROTEIN DELIVERY TRIAL AND FINALLY STEVE GILL IS STARTING A TRIAL ON DIRECT DELIVERY BUT I HAVE BEEN AROUND A WHILE. GENE DELIVERY AND PROTEIN DELIVERY MOLECULES MIGHT BE SOMETHING WE WANT TO PUT ON THE LIST AS WELL WITH TRANSPLANTATION, THE AGREEMENT ON THE PANEL AN THE GROUP. >> ALL THE ROADS ARE WINDING TO DRUG DISCOVERY LIKE EVERYBODY -- LIKE THE THANK EVERYBODY FOR THEIR QUESTIONS AND THEIR COMMENTS. THANK YOU. [APPLAUSE] >> SO THE LAST SESSION FOR TODAY IS SCHEDULED FOR HALF HOUR, PARKINSON'S DISEASE RESEARCH EVALUATION, A MULTI-STAKEHOLDER PERSPECTIVE. THIS EFFORT IS LED BY MS. AMY COMSTOCK RICK AND BETH ANN SIEBER. AMY WILL TAKE THE PODIUM. WELCOME. >> I'M SORRY TO TO IT THIS TO TO YOU, NO ENDING TIME, IT'S SCHEDULED FOR ONE HOUR. BUT THERE'S NO WAY WE CAN GET THROUGH ALL THE MATERIAL THAT YOU HAVE IN HALF AN HOUR. THIS SESSION IS SWITCHING GEARS. THIS PANEL WILL STEP BACK AND LOOK AT HOW WE ASSESS RESEARCH AND HOW WE DETERMINE WHAT IS SUCCESSFUL RESEARCH, IN THE RESEARCH ENTERPRISE AND NARROWER CONTEXT OF INDIVIDUAL RESEARCHERS AND INDIVIDUAL RESEARCH PROJECTS. MOST WOULD AGREE NO RESEARCH PROJECT IS SUCCESSFUL IN ISOLATION, EVEN THE MOST BASIC RESEARCH DISCOVERIES BY INDIVIDUAL ACADEMIC RESEARCHERS ARE PRIOR DISCOVERIES BY OTHERS AND WE HOPE WILL BECOME BILL ON THE WORK OF INDIVIDUAL RESEARCHERS AND FUNDERS PUBLIC AND PRIVATE AND USUALLY AT LEAST ONE NOT OFTEN MORE INDUSTRY PARTNER. YOU HAVE NO UNIVERSAL WAY DETERMINING EITHER WHETHER THE FULL A TO Z BASIC MARKET APPROVAL TO PIPELINE IS FUNCTIONING AS EFFECTIVELY AS IT MIGHT NOR WHETHER INDIVIDUAL GOALS OF RESEARCHERS STAKE HOLDERS ALONG THE WAY ARE THE APPROPRIATE MOTIVATORS FOR SUCCESSFUL RESEARCH ENTERPRISE. THE BEAR PRIZE IS TOO LARGE, COMPLEX AND TRADITION BOUND TO IDENTIFY AND IMPLEMENT SUPERIOR METRICS AND UNSENTIVES PARTICULARLY ONES THAT CAN ALSO KEEP PACE WITH THE RAPIDLY CHANGING TECHNOLOGY AND SCIENTIFIC OPPORTUNITIES. IN THIS PIECE THEY ARGUE FOR CREATION OF NEW INSTITUTION I READ IT IN NEW FEDERAL AGENCY LOOSELY CONNECTED TO NIH TO DEVELOP EFFECTIVE ARGUMENTS ABOUT THE VALUE OF BIOMEDICAL RESEARCH TO SOCIETY I DO T IN THE BELIEVE A NEW FEDERAL AGENCY IS THE WAY TO GO HERE. AND INCENTIVES THAT RESEARCHERS STAKEHOLDERS CARRY DO INFLUENCE THE DIRECTION OF RESEARCH AND CAN PROMOTE BOTH WHICH WE NEED VERY MUCH IN THE PARKINSON'S DISEASE COMMUNITY. WE HEARD IT THROUGHOUT THE DAY TODAY WHERE THE QUESTION SOMEONE IS ASKING JUST CAME UP IN THE LAST SESSION MUCH MORE ELEGANTLY THAN I'M ANT TO SAY, BUT WHO WOULD DO THIS. WHO WOULD HAVE THE INCENTIVE TO CONDUCT THIS RESEARCH. THE PURPOSE OF THIS PANEL IS TO DISCUSS MANY FINANCIAL ORGANIZATIONAL AN CULTURAL INCENTIVES THAT EXIST FOR THE STAKE HOLDERS IN THE VARIOUS STAGES OF RESEARCH AND HOW ACKNOWLEDGING AND MEETING THOSE DIFFERING INCENTIVES MIGHT HELP US COLLECTIVELY COLLABORATE BETTER. I WANT TO START BY TAKINGING A MINUTE TO LOOK AT A BRAINSTORM SLIDE MANY STAKE HOLDERS FROM A PATIENT PERSPECTIVE WE SEE IN THE RESEARCH ENTERPRISE AND MANY MOTIVATORS THAT INDIVIDUALS WITH MULTIPLE PERSPECTIVES CARRY MANY COULD ADD OTHERS TO THIS LIST BUT IT'S ALL TO SAY EVERYONE IN THIS CLOUD HAS OOH A ROLE TO PLAY IN THE PARKINSON'S RESEARCH ENTERPRISEND FAIR TO SAY ALL THESE ARE REPRESENTED IN THIS WORKSHOP NOW. WHEN WE LOOK AT MOTIVATORS, POTENTIAL MET INVESTIGATORS FOR ALL THESE, MOST STAKEHOLDERS ON THE BELIEVEIOUS SLIDE, THEY DOWN -- PREVIOUS SLIDE, ARE DRIVEN BY MORE THAN ONE NO ONE IS DRIVEN BY ALL OF THEM. IT'S ALSO FAIR TO SAY NONE OF THESE INDIVIDUAL MOTIVATORS IS GOOD OR BAD. BUT IF THEY ARE MOTIVATORS THAT INFLUENCE RESEARCH DIRECTION AND COLLABORATION, I WOULD SUGGEST WE HAVE TO ASSESS THAT ACKNOWLEDGE THAT, AND ASSESS THEM IN THE LARGER CONTEXT HOW THEY ACTUALLY DO INFLUENCE THE OVERALL VALUE OF BIOMEDICAL RESEARCH. I THINK WE HAVE TO -- BRING ALL THIS BACK TO CONTEXT THE MAIN QUESTION FOR TODAY AND TOMORROW WHEN WE LOOK AT THE PRIORITIZED RECOMMENDATIONS THAT COME OUT OF THIS WORKSHOP, WHAT ARE WE DOING TO INCENTIVIZE IN THE PARKINSON'S COMMUNITY TO ENSURE RECOMMENDATIONS ACTUALLY DO MOVE FORWARD. WE WILL START THAT CONVERSATION WITH ONE SPEAKER FROM ASSOCIATION OF AMERICAN MEDICAL COLLEGES, AAMC ASKED RAND EUROPE TO CONDUCT A DETAILED SYNTHESIS OF EXISTING AND PREVIOUSLY PROPOSED FRAMEWORKS AND INDICATORS THE PURPOSE OF THIS REVIEW IS TO STIMULATE DEBATE AMONG U.S. POLICY MAKERS AND LEADERSHIP MEDICAL SCHOOLS AN TEACHING HOSPITALS HOW TO MEASURE OUTCOME OF RESEARCH AND U.S. TAXPAYERS AND OTHERS FOR INVESTMENT ON RESEARCH AND TO MAKE T MORE PERSONAL SO WE CAN ASSESS WHETHER THE RESULT OF PARKINSON'S DISEASE COMMUNITY IS WELL WORTH THE INVESTMENT. RECEIVE WITH THAT I WOULD LIKE TO INTRODUCE ANN BONHAM, WHO IS CHIEF OF THE AMERICAN MEDICAL COLLEGE. >> THANK YOU VERY MUCH. WHEN AMY ASKED ME TO TALK TO THIS GROUP SHE SENT OUT A COUPLE OF QUESTIONS, I L ONLY GOING TO REFRAIN THOSE A BIT. AS A RESEARCHER WHAT WOULD YOU CONSIDER YOUR RESEARCH TO BE SUCCESSFUL AND P WHAT METRICS WOULD YOU USE? ONE CAN ASK THE QUESTION OF VARIOUS STAKEHOLDERS AS SUCCESSFUL AND WHAT METRICS WOULD THEY USE. THIS IS WHAT STIMULATED OUR THINKING ABOUT A YEAR AGO AT THE AMC TO THINK ABOUT RESEARCH EVALUATION WITH A DIFFERENCE LENS. MANY CAN ARGUE WEB DOING RESEARCH EVALUATION FOR A LONG TIME AND THE ANSWER IS BOTH YES WE HAVE AND NO WE HAVEN'T. WE HAVE CONSIDERED OUR TWO ACADEMIC METRIC AND I AM A BASIC SCIENTIST, I COME FROM THE BASIC SCIENCE BACKGROUND AND I WELL KNOW THE VALUE OF PEER REVIEW AND THINKING METRICS INCLUDING THE VOLUME OF GRANT FUNDING FROM NIH AND OTHER AGENCIES AS WELL AS PEER REVIEWED PUBLICATIONS AN PAPERS. WE'RE CLEARLY NOW AT A POINT WHERE THAT IS NOT ENOUGH. NOT THAT IT'S INSUFFICIENT BUT IT'S SIMPLY NOT ENOUGH. AND WE HAVE COME TO THIS, I THINK OVER THE PAST COUPLE OF YEARS BY RECOGNIZING SOME STAKEHOLDERS THE PATIENTS AND THE FAMILIES, ARE BECOMING INCREASINGLY FRUSTRATED WITH THE SLOW PACE OF BIOMEDICAL RESEARCH, I DARE SAY MANY IN THIS ROOM ALSO LIKE TO SEE THAT PACE QUICKEN BUT HAVE WE BECOME STUCK IN SAYING WELL BECAUSE THE PACE IS SO SLOW, THE ONLY WAY TO EVALUATE RESEARCH IS LOOKING IN A REAR-VIEW MIRROR 14 YEARS FROM NOW, THAT WON'T WORK IN THE FUTURE. WE DO HAVE NEW TECHNOLOGIES, NOT JUST NEW SEQUENCING TECHNOLOGIES BUT THERE'S OPEN SCIENCE TECHNOLOGY WHERE MANY PEOPLE, LIKE THE DENOT PHYSICIAN OF DATA, MANY HAVE ACCESS DEMOCRATIZATION OF DATA. MANY WONDER WHY THEY OTHER NOT QUERYING THE DATA FOR THE RESEARCH AND THEY MIGHT HAVE A GOOD POINT. THERE IS NOW AN INCREASING ENGAGEMENT OF PATIENT ORGANIZATIONS INCLUDING PARKINSON GROUP, REALLY LOOKING AT THE RESEARCH THAT WE DO IN BASIC SCIENCE AS WELL AS CLINICAL AND TRANSLATIONAL SCIENCE SAYING ARE WE DOING THE RIGHT THINGS AND ARE WE USING THE RIGHT METRICS. THEN OF COURSE THE NATIONAL ECONOMIC AND POLITICAL DEBATE WHICH LED SOME IN CONGRESS THAT THINKS THEY SHOULD INSERT THEMSELVES TO DECIDE METRIC FOR RESEARCH. SO THESE ISSUES AND CIRCUMSTANCES ARE NOT JUST INSIDE THE BELTWAY IN DC BUT SIMILAR CONVERSATIONS ARE ACTUALLY GOING ON IN MEDICAL SCHOOLS ACADEMIC INSTITUTIONS ACROSS THE COUNTRY. AND A NUMBER OF DEANS RESEARCH LEADERS SAID TO US THEIR LOCAL STAKEHOLDERS ARE ALSO ASKING THEM THE TO DEMONSTRATE VALUE OF MEDICAL RESEARCH BOTH BUT BASIC AND CLINICAL RESEARCH IN THEIR INSTITUTION. IF THIS IS THE CASE, WE SAID TO THINK RESEARCH EVALUATION WHY HAS IT TAKEN SO LONG AND WHY HAVEN'T WE DONE THIS? ONE THING, RESEARCH EVALUATION IS NOT EASY, IT'S NOT SOMETHING EVERYBODY CAN EASILY DO. THE METHODOLOGIES ARE COMPLEX THEY REQUIRE CONCEPTUAL UNDERSTANDING OF UP SIDES AND DOWN SIDES, THAT MAKES IT MUCH MORE BLURRY THAN WE LIKE TO THINK. MANY IN THE RESEARCH COMMUNITY HAVE LONG WORRIED EVALUATION METHODS DEYOUR WILL DISREGARD THE INEVITABLE TIME LAG FOR RESEARCH AND CAN BECOME AN UNFUNDED MANDATE TO CHECK THE BOX. PROVIDE THE AVENUE FOR MEANINGLESS REPORTING OF METHODS AND METRICS THAT DONE MAKE SENSE, THERE'S ALSO CONCERN NEW EVALUATION METHODS WILL BECOME A WAY TO ALLOCATE FUNDING AND DIMINISH FUNDING FROM BASIC RESEARCH. NOTWITHSTANDING THESE CONCERNS, RESEARCH EVALUATION IS NOT GOING AWAY. MANY WILL PROBABLY REMEMBER THE RECENT ISSUE OF NATURE ON THE COVER THERE WAS MEASURING RESEARCH IMPACT. AT NIH THE SCIENTIFIC MANAGEMENT REVIEW BOARD IS CHARGED WITH EVALUATION METHODOLOGIES FOR NIH FUNDED RESEARCH. FROM RAND EUROPE THERE IS THE QUOTE EVALUATION IS GOING TO HAPPEN, IT'S ALWAYS GOING TO HAVE DOWN SIDE AND UP SIDES BUT BY GETTING AHEAD OF CURVE WE WANT TO ENSURE WE TAKE ADVANTAGE OF AS MANY OF THOSE UP SIDES AS POSSIBLE. SO AT THE AMC WE UNDERTOOK THIS THINKING MOSTLY FROM THE VANTAGE POINT OF MEDICAL SCHOOL AND TEACHING HOSPITALS, AS AMY SAID WE DO ENGAGE RAND EUROPE TO UNDERTAKE THIS STUDY. THE FIRST WAS TO HAVE THEM DO AND IN DEPTH LOOK AT 14 MAJOR RESEARCH EVALUATION INITIATIVES THROUGHOUT EUROPE TO PROVIDE DETAILED ANALYSIS. AND TO COME WITH US, BRING THAT REPORT TO US, THE SECOND STEP THEN WAS TO ENGAGE STAKEHOLDER INPUT SO WE HAD THREE PANELS, A BASIC SCIENCE PANEL, A CLINICAL OUTCOMES AND IMPROVEMENT SCIENCE PANEL THEN HEALTH EQUITY RESEARCH PANEL. YOU MIGHT ASK WHY DID YOU START WITH THESE PANELS? WE FELT LIKE WE NEEDED TO START WITH SMALL GROUPS OF TEN EXPERTS INCLUDING EVALUATIVE EXPERTS IN THOSE PANELS AND BRING THEM TOGETHER AT A LATER POINT TO VIEW. THE PURPOSE OF THE PANELS WAS TO DO FOUR THINGS. ONE IS WE WANTED TO BRING THEM TOGETHER WITH RAND EVALUATION AND WE USE THE RAND TEAM BECAUSE THEY HAVE AN INTERNATIONAL REPUTATION. THREE YEARS AGO THEY JUST DID RATHER SOPHISTICATED ANALYSIS MENTAL HEALTH RESEARCH OUTCOMES AND IMPACT. THEY SEEM TO BE THE RIGHT TEAM. IN THESE WORKSHOPS, WE WANT THE EXPERTS TO IDENTIFY GAPS IN WHAT WE'RE MEASURING AND SUCCESS FROM THEIR PERSPECTIVE; WE WANTED THEM TO INFORM RAND ABOUT BIOMEDICAL RESEARCH IN THE U.S. AND P HAVE RAND INFORM THEM ABOUT THE NUANCES OF USING A RESEARCH EVALUATION. WE WANTED TO BE ABLE TO MITIGATE INCENTIVES IN ACADEMIC MEDICINE. THE LEARNING FROM THIS, I'LL PRESENT FIVE OR SIX LEARNINGS THE FIRST CONCLUSION WAS REGARDLESS OF METRICS IN THE AREA OF RESEARCH, IN THE END THIS HAS TO BE ABOUT IMPROVING THE HEALTH AND WELL BEING AND DIGNITY AND RESPECT FOR PATIENTS. SO THAT'S THE FIRST OVERRIDING CONCLUSION. THE SECOND ONE WHEN YOU THINK RESEARCH EVALUATION, THERE'S NO MAGIC BULLET BUT WE HAVE TO START WITH A CLEAR FOUNDATION OF THINKING, MAYBE AROUND SIMPLE LOGIC MODEL. THE INPUT MONEY FROM NIH OR OTHER AGENCIES, EQUIPMENT SKILL, MATERIALS OR SUPPLIES AND THE TIME INVESTMENT. OUTPUT. NEW DATA, NEW SKILLS, NEW TECHNIQUE, NEW TECHNOLOGIES, NEWLY TRAINED SCIENTISTS, OUTCOMES CAN BE CHANGES IN POLICY, NEW PRODUCTS, NEW KNOWLEDGE, OR CHANGES IN PRACTICES OR EVEN NEW PRACTICES. FINALLY THE IMPACT. THOSE HEALTH BENEFITS AND ECONOMIC BENEFITS TO SOCIETY. HAVING INPUT OUTPUT OUTCOMES AND IMPACT, THE IDEA WAS TO PUT A POINT ON THE METRICS. THERE ARE A NUMBER OF METRICS VALIDATED NO ONE SUGGESTS WE ABANDON. CASE STUDIES, ECONOMIC ANALYSIS. MODEL SITE VISIT, SOCIAL NETWORK ANALYSIS. THE WAY WE EMPLOY THESE AND THE NUANCES WE USE IN EMPLOYMENT OF THESE, MIXING AND MATCHING AND TARGETING TO THE AUDIENCES, THAT'S WHAT WE NEED TO GET BETTER AT T CONCLUSION OF THE PANEL. RAN RECOMMENDED THERE ARE FOUR As RESEARCH EVALUATION AND THE PANEL THOUGHT THESE WERE GOOD. FIRST A IS ALLOCATION. ALLOCATION OF FUNDS. RESEARCH EVALUATION IN EUROPE IS LARGELY ALLOCATION OF FUNDS. THAT'S NOT SOMETHING WE'RE PARTICULARLY INTERESTED IN BUT ONE OF THE As. THE OTHER A IS THE ANALYSIS, THE ANALYSIS OF HOW FUNDS ARE SPENT. ACCOUNTABILITY. THIRD ARC. ACCOUNTABILITY FOR HOW FUNDS ARE USED AND ADVOCATE ADVOCACY FOR CONTINUED OR MORE FUNDING. SO THE FOUR As COVER THE AREAS THE PANEL THOUGHT IMPORTANT THOUGH THEY HAD DIFFERENT EMPHASIS DEPENDING ON THE TYPE OF RESEARCH. AT THE SAME TIME WE THINK ABOUT THE AREAS OF RESERGE, I THINK THIS WOULD APPLY TO SOME OF WHAT YOU'RE THINKING ABOUT IN TERMS OF THE CLINICAL RESEARCH TRANSLATIONAL AND THE FUNDAMENTAL DISCOVERY. THERE ARE SOME DIFFERENCES, RATHER THAN AS I SAID A SINGLE BULLET, A MENU OF TOOLS OR COOK BOOK MAYBE MORE VALUABLE IN THINKING ABOUT RESEARCH EVALUATION. I WANT A FINER POINT. STAKEHOLDER GROUPS THAT VARY FROM GROUP TO GROUP. FOR EXPERT PANEL ON IMPROVEMENT RESEARCH THEY SAW THE HEALTH SYSTEM LEADERSHIP AND BOARD OF DIRECTORS AS THEIR MAJOR STAKEHOLDER. SO WHEN THEY WERE THINKING ABOUT METRICS INCLUDED, THIS IS QUOTE. SOMETIMES WE HAVE TO ACKNOWLEDGE THE REALITY. WHAT DRIVES OUR CONVERSATION IS REALLY WHAT DRIVES OUR BOTTOM LINE. SO METRICS WOULD INCLUDE RESEARCH THAT IMPROVES EFFICIENCY PRESERVES THE BOTTOM LINE, INCREASES PATIENT SAFETY OR INCREASES PATIENT SATISFACTION. CONTRAST TO BASIC SCIENCE PANEL, MAJOR STAKEHOLDERS AS FUNDERS INSTITUTIONAL LEADERS AND ACADEMIC COMMUNITY. THIS IS A QUOTE FROM THEM. WE DON'T HAVE D&O A WOO GOOD JOB MAKING THE CASE FOR BASIC SCIENCE USING METRICS THAT MATTER TO OTHERS INCLUDING TO PATIENTS. FOR EXAMPLE, WOULD THE ABILITY TO RESTRUCTURE THE RESEARCH COMMUNITY TO ADVANCE LATEST TECHNOLOGY, BE IMPORTANT METRIC? WOULD TRAINING FOR THE FUTURE MOVE TO NETWORK ANALYSIS AN SYSTEMS THINKING BE A METRIC? SHOULD WE THINK NET WORK ANALYSIS OF COLLABORATIONS INCLUDING WITH BIOINFORMATICS AND OTHERS TO BE A METRIC. SHOULD WE THINK ABOUT A ME TRICK FOR BASIC SCIENCE THAT TAKES ADVANTAGE OF EXISTING DATA REGISTRIES? NOT JUST RESEARCH SO THESE ARE THE TYPES OF ISSUES BROUGHT UP. FINALLY THEY RECOGNIZE IN THE END ABSOLUTE VALUE HERE, HAS TO BE CONSIDERED TO THE PATIENT AND THAT WHILE ALL THIS MOVES FORWARD, AT THE END THE HELP IS IMPACT ON THE PATIENTS. I WANT TO CLOSE BY JUST BRINGING UP A COUPLE OF POINTS. WHERE WE ARE RIGHT NOW. WE FINISHED WITH A THIRD PANEL IN DECEMBER. WHERE RAND SYNTHESIZES THE SIMILAR LAWYERTIES AN DITCHES AND APPROACH AND TOOLS ACROSS ALL PANELS BRING THEM BACK TOGETHER AND WE HOPE TO USE AND PILOT THESE TO INSTITUTIONS. THIS IS NOT JUST CHECKING THE BOX, OR DISCARDING RESEARCH EVALUATION TECHNIQUES THAT WE USE BUT IT'S RATHER THINKING ABOUT A BROADER SET THAT RECOGNIZES THE STAKE HOLDERS, THAT YOU CAN SEE THE STAKEHOLDERS VARY FROM GROUP TO GROUP. WE HAVE BEEN MEASURING SUCCESS FOR OURSELVES AND NOT MEASURING THE SUCCESS FOR OTHERS. IN THINKING METRICS, I'LL QUOTE WHAT FRANCIS SAID A COUPLE OF WEEKS AGO IN IN THIS ON ED PIECE IN WASHINGTON POST, THE ECONOMIC BENEFITS OF NIH FUNDING OBVIOUSLY INCLUDE RETURN ON INVESTMENT OF RESEARCH GRANTS TO LOCAL ECONOMIES, AND COST SAVINGS FROM DECREASEDDED DISEASE BURDENS BUT BEYOND, FROM THE MILLIONS OF SICK PEOPLE AWAITING TREATMENT AND CURES THE INVESTMENT NIH MISSION IS PRICELESS, IT'S AN INVESTMENT IN HOPE. I'LL END WITH AN ALLEGORY AMY MADE. AMY IS ON THE,AMC ADVISORY PANEL FOR RESEARCH AND I HAVE A QUOTE, I HAVE LOTS OF QUOTE BUT IN IS ONE YOU'LL SHARE. SHE SAID THAT WHEN TOYOTA IS DRESSING ADDRESSING ITS BOARD SHAREHOLDERS, THE NTA THE LINE WORKERS ARE IN CONSUMERS. IT USES DIFFERENT MESSAGES, IT SHOULD BE NO DIFFERENT FOR THE RESEARCH IMMUNITY. WE NEED A DIFFERENT LANGUAGE AND DIFFERENT MESSAGES AND DIFFERENT MEASURES DEPENDING WHICH SEGMENT WE'RE ADDRESSING. SO IN THE IF THE RESEARCH ENTERPRISE WHO WE ARE, IF WE DON'T MEASURE AN COMMUNICATE IMPACT IN A LANGUAGE THAT MAKES SENSE TO ALL OF OUR STAKEHOLDERS, INCLUDING PATIENTS, AREN'T WE FAILING IN ONE OF OUR ESSENTIAL RESPONSIBILITIES FOR THE WORK WE DO? I'M HAPPY TO ANSWER ANY QUESTIONS, WE HAVE A PANEL COMING UP AM I STAYING OR GO SOMETHING YOU'RE STAYING. >> I KNOW WE'RE STANDING BETWEEN YOU AND PROBABLY A WINE RECEPTION WHICH IS USUALLY THE CASE AT 4:30. IF THE PANEL WANTS TO COME UP. >> WE'RE IN A NEW GOVERNMENTER RA. THERE IS -- IF THERE IS WINE RECEPTION I CERTAINLY WASN'T INVITED. WE ARE NOW GOING TO MOVE TO A PANEL SESSION. AND FROM THIS LIST OF PANELISTS WE ARE TRYING TO REPRESENT VARIOUS STAKEHOLDER POPULATIONS ON THE SLIDE. STARTING OVER THERE, OBVIOUS -- DAVID SULZER, OBVIOUSLY DR. LANDIS NEEDS TO INTRODUCTION. BERNARD RAVINA. ARE YOU ON PHONE? Q. I AM. >> YOU HAVE TO SPEAK UP A LITTLE BIT JUST TO LET YOU KNOW. WHEN YOU SPEAK, BIOENGINE REPRESENTING INDUSTRY. TODD SHERER FROM THE PRIVATE FOUNDATION AND ANN BONHAM FROM THE ARCMC FOUNDATION. I DID ASK EACH OF OUR PANELISTS TOP THINK ABOUT THESE QUESTIONS BEFORE AS THEY EACH REPRESENT ONE STAKEHOLDER AREA, THINK ABOUT THESE QUESTIONS IN TERMS OF THEIR REMARKS AND ASK THEM TO DO TWO THINGS. FIRST REACT A LITTLE BIT TO WHAT ANN PRESENTED AND TALK INCENTIVES AN MOTIVATOR S FROM THEIR PER P SPECKTIVE OF THE WORLD THEY LIVE IN. ONE OF MY CONCERNS WHAT WE WILL NEED TO TALK ABOUT HERE IS IN THE RESULTS RECOMMENDATIONS FROM THIS WORKSHOP, IF THERE ARE SOME WHERE THERE AREN'T -- IF THERE ARE SOME OR TOO MANY THAT THERE AREN'T ENOUGH ENTITIES MOTIVATED TO FULFILL THESE RECOMMENDATIONS, WHAT ARE WE GOING TO DO ABOUT THAT? ARE WE CONFIDENT EACH OF THESE WILL MOVE THROUGH? SO I ASK YOU THE TAKE A FEW MINUTES AN COMMENT ON WHAT ANN SAID ABOUT VALUATION IS COMING, SOUND VERY PAUL REVERE LIKE. AN TALK ABOUT THAT FROM YOUR PERSPECTIVE AND WHERE YOU SIT AND WHAT YOU TRY TO DO TO INCENTIVIZE MOVEMENT TOWARD BETTER TREATMENTS ABOUT CURES FOR PARKINSON'S FROM YOUR PERSPECTIVE. THANKS. I'LL TAKE THE BLIND SPOT OVER HERE. >> SO WHAT MOTIVATES US AS BASIC RESEARCHERS AND WHERE DO WE STAND IN TERMS OF THERAPY DEVELOPMENT, WE ARE NOT A HUMBLED CROWD SPEAKING FOR MY FELLOW BASIC RESEARCHERS, WE FIRMLY BELIEVE OUR WORK SETS UP THE FUTURE FOR TREATMENT WE FEEL SHORT SHIFTED, WE SEE SOME OF THE -- THERE ARE LIMITED RESOURCES FOR RESEARCH IN PARKINSON'S DISEASE. IT'S QUITE DIFFICULT TO CONTINUE OUR WORK, IT'S BEEN PARTICULARLY HARD THE LAST SEVERAL YEARS AS YOU KNOW, VARIOUS SEASONS SITTING IN THE BELLY OF THE BEAST. BUT WE'RE ALSO SITTING IN ONE OF THE LAST PASTIONS OF REALITY BASED ANALYSIS IN THE WASHINGTON D.C. AREA. NOT BEEN EASY FOR BASIC RESEARCH LATELY BUT IF WE LOOK AT IF WE LOOK AT THE WORK USED IN THE CLINIC, WE'RE STUDYING DISEASES LIKE PARKINSON'S DISEASE,TY TREAT PATIENT, WE ARE INTERESTED IN NATURE, OTHERWISE WE WOULDN'T BE BASIC RESEARCHERS. THE REASON WE WORK IN THESE FEELS IS TO TREAT PATIENTS. IF WE MAKE A LIST OF THE SORTS OF TREATMENTS USED THESE DAY, EL DOPA. I BROUGHT A ONE PAGE PAPER HISTORY WHO IS RESPONSIBLE ALONG WITH GEORGE (INAUDIBLE) FOR INTRODUCING EL DOPA, IT GOES THROUGH THE STEP BY STEP POINTS THAT TOOK THE TEN YEARS TO DEVELOP IT FROM DISCOVERY FROM CATH LEAP MONTAGUE FROM THE CENTRAL NERVOUS SYSTEM IN 1957 THROUGH THE WORK BY CARLSON AND (INAUDIBLE) TO INTRODUCE EL DOPA AND GEORGE CASSIUS TEN YEARS LATER ORAL ADMINISTRATION OF EL DOPA. WE HEARD NUMEROUS TIMES THE GOAL STANDARD, IF WE LOOK AT USE OF DOPAMINE AGONIST THERE'S A SIMILAR STORY FROM DONALD (INAUDIBLE) AND FROM GEORGE THAT TOOK 15 YEARS, I WAS REFERRING TO DR. DELONG AND BERGMAN WHO BASED THEIR WORK FOR DEEP BRAIN STIMULATION ON SUBTHALAMIC NUCLEUS, THAT CAME OUT OF EARLY WORK BY (INAUDIBLE) HERE AT NIH WHO IS THE FELLOW -- WHOSE LAB DISCOVERED THE MPTP MODEL, PHYSIOLOGY. AND THAT TOOK INTRODUCE SOME PATIENTS IN 1995. SO 25 YEARS BUT THAT'S HOW LONG FOR BASIC RESEARCH TO REACH THE CLINIC. I DON'T THINK THERE'S -- ALTHOUGH THAT'S WAY TOO SLOW FOR PATIENTS, I DON'T THINK THEREgS A LOT OF REASON TO SUSPECT BECAUSE WE HAVE BIGGER HARD DRIVES THAT WE'RE GOING TO SOMEHOW MAGICALLY GET TO THESE GOALS MORE QUICKLY. NOW, OUR FRUSTRATION WITH -- OUR VALUE AS RESEARCHERS AND WHAT WE LOCK FOR IS SIMPLY TO KEEP OUR WORK GOING. WE'RE MOTIVATED BY BEING ABLE TO DO OUR RESEARCH WITH THE IDEA THAT WE'LL BOTH UNVEIL NATURE AND BE ABLE TO TREAT PATIENTS. AND THE THREE EXAMPLES I GAVE, EXAMPLES I HAVE CHOSEN CAREFULLY, WE ARE CURRENT TREATMENTS FOR PARKINSON'S DISEASE, SUCCESSFUL SINCE THERE'S RATE LIMITING FACTORS ON -- THERE AREN'T INFINITE RESOURCES TO GO TO THE STUDY OF THESE DISEASES, WE HAVE TO LOOK AS PEOPLE THAT BELIEVE IN QUANTITATIVE ANALYSIS, WE HAVE TO LOOK AT WHAT WORKS, THIS HAS WORKED. IT'S DOING THE HARD WORK IN THE LABORATORY AND THEN EVENTUALLY BRINGING IT TO PATIENTS. I DON'T THINK THAT'S GOING TO CHANGE OVER THE YEARS. OUR FRUSTRATION AND WHAT WE LOVE ABOUT OUR WORK AND THE VALUE, WHAT'S THE TERM WHAT WE CONSIDER TO BE SUCCESS IN A SENSE TO DO IT AT ALL. TO THE EXTENT DR. LANDIS AND TODD AND OTHER PEOPLE CAN HELP US WITH THAT, WE'RE APPRECIATIVE. WE THINK IT'S ABSOLUTELY NECESSARY FOR THE FUTURE OF THE RESEARCH. I THINK SPEAKING FROM MY OWN PERSONAL EXPERIENCE, ONE OF THE BUG BOOS OF OUR WORK IS WHEN WE FINE SOMETHING AND WE DO THE PAY SICK RESEARCH, IT'S VERY,VERY DIFFICULT TO BRING TO THE NEXT STEP TOWARDS CLINIC. I'M HAPPY TO GIVE EXAMPLES THAT COME UP LATER IN THE CONVERSATION. I DON'T WANT TO HOG ANY MORE TIME BUT IF WE HAVE BEEN TRYING TO ADVOCATE EXAMINING A NEW THERAPY TO CAUSE REGROWTH OF SURVIVING AXONS OF DOPAMINE SYSTEM IN THE DORSAL STRIATUM YOU CAN GET GOOD RESPONSE AND CORRECTION OF BEHAVIORAL DEFICITS, NEW PAPER BY SMITH ET AL IN OUR GROUP IN JOURNAL OF NEUROSCIENCE A COUPLE OF MONTHS AGO. WHEN WE TRY TO FIGURE HOW TO BRING TO PATIENTS WE RAPIDLY REACH A BRICK WALL PLASHINGLY WORKING WITH PHARMACEUTICAL INDUSTRY THAT WE HAVE TO WORK WITH. I KNOW HAVING SPOKEN TO PEOPLE ABOUT OTHER EFFORTS THESE STATES RUNNING INTO THE SAME KINDS OF PROBLEM SO THAT IS A GOAL THAT I HOPE THE COMMUNITY CAN FOCUS ON. I COWANT TO SAY ONE MORE THING BEFORE TURNING IT TO THE OTHER SPEAKERS. THAT IS, ONE THING THAT'S VERY IMPORTANT FOR BASIC RESEARCHERS IN THE FIELD AS A WHOLE IS THAT WE GET A CHANCE TO COMMUNICATE. THANKFULLY THE GORDON CONVERSATION YOU ALL KNOW HAS INVITED US TO HAVE THE FIRST GORDON CONFERENCE ON PARKINSON'S DISEASE, THAT WILL BE AT THE END OF JUNE, A YEAR AND A HALF FROM NOW IN 2015, IT WILL BE THE FIRST CONFERENCE IN PARKINSON'S DISEASE, NOT ONLY BAYING IS RESEARCHERS WILL COME TO THIS BUT ALSO PEOPLE CLINICS FROM THE PHARMACEUTICAL INDUSTRY, POLICY MAKER, PEOPLE FROM THE PATIENT ORGANIZATIONS AND FOUNDATIONS, SCIENCE ADVANCES FASTER AND MORE EFFICIENTLY IF WE GET A CHANCE TO GO BEYOND READING PAPERS AND WALK UP TO SOMEONE AND SAY WELL, REALLY? DID THIS REALLY WORK? HOW DID IT WORK? WHAT ARE THE PROBLEMS WITH -- WHAT ABOUT YOU AND I, WE HAVE A DISAGREEMENT ABOUT HOW THIS PARTICULAR STEP MIGHT WORK. WHY DON'T WE PUT OUR HEADS TOGETHER AND DESIGN THE BEST EXPERIMENT. SO THAT WILL BE JUNE 28, 2015, YOU'LL BE THE FIRST CHAIR AND ANDY SINGLE TOPOWILL BE THE FIRST CO-CHAIR RUNNING THE SECOND MEETING IN 2017. >> THANK YOU, DAVID. I'M GOING TO TURN TO YOU, STORY AND ASK FOR THE FEDERAL FUNDING AGENCY PERSPECTIVE HOW YOU DEFINE SUCCESS. VARIES BETWEEN BASIC CHANCE TRIGGAL AND CLINICAL. BUT I'LL ALSO ADD A LAYER ON THAT AS WELL. HOW DO YOU DEFINE SUCCESS FROM THIS MEET SOMETHING WILL IT BE RECOMMENDATIONS 36 RECOMMENDATIONS? OR I'M SORRY, WILL IT BE ASSESSED DOWN THE ROAD WERE THOSE APPROPRIATE RECOMMENDATIONS AND DID THEY MOVE THE FIELD FORWARD. YOU HAVE THREE MINUTES. I SPENT THE REST OF THE DAY AT THE LEADERSHIP FORUM OF IC DIRECTORS AND THE MORNING WAS CONSUMED WITH PEER REVIEW AND THE GRANTS WE FUN AS A CONSEQUENCE OF PEER REVIEW ARE THE BEST POSSIBLE SCIENCE WE COULD BE FUNDING WAS VERY INTERESTING DISCUSSION AND QUITE WIDE RANGING. WHAT AMY IS ASKING IS NOT WHAT DO WE FUND BASED ON PEER REVIEW BUT WHAT ARE THE OUTPUTS FUNDED AND FOR NINDS IT'S A COMPLEX PROBLEM BECAUSE WE'RE RESPONSIBLE FOR MANY DISEASES IN ADDITION TO PARKINSON'S DISEASE AN EACH ONE OF THOSE DISEASES IS IN A DIFFERENT STAGE UNDERSTANDING TRANSLATION AN CLINICAL EFFORT. I WOULD SAY THAT FOR STROKE WE HAVE MADE EXTRAORDINARY PROGRESS REDUCING THE INCIDENCE OF STROKE AND DEATH FROM STROKE OVER SOME PERIOD OF TIME AS A CONSEQUENCE OF CONTROLLING HYPERTENSION AND HAVING ACUTE TREATMENT BUT THERE ARE MANY OTHER DISEASES FOR WHICH INCLUDING PARKINSON'S FOR WHICH WE SIMPLY DON'T HAVE THAT SAME KIND OF SUCCESS. AT NINDS WE HAVE OVER SEVERAL YEARS AS THE BUDGET HAS GOTTEN TIGHTER AND TIGHTER, FOCUSED NOT SO MUCH ON THE GLOBAL ISSUE OF SUCCESS BUT LOOKING CAREFULLY AT INITIATIVES THAT WE INSTITUTED TO MAKE SURE INITIATIVES WERE ACTUALLY SUCCESSFUL THE CRITERIA WE USED IS THERE WAS AN INITIATIVE, THIS WAS THE GOAL, DID WE REACH THE GOAL. OF THE INITIATIVE. IF WE DID MAYBE WE SHOULD STOP FUNDING THAT PARTICULAR ACTIVITY. IF WE DIDN'T REACH THE GOAL IS IT WORTHY, P IF IT IS WORTHY AND WE HAVEN'T REACHED IT WITH MECHANISMS WE HAD PUT IN PLACE, MAYBE WE NEED TO THINK ABOUT ALTERNATIVE MECHANISMS. BY DOING THE THIS ANALYSIS AT BOOTS ON THE GROUND LEVEL, WE HAVE BEEN ABLE TO USE FUNDS MORE EFFECTIVELY. THE FIRST EXAMPLE I GIVE YOU IS GEN SAT, AN EFFORT TO CREATE MICE THAT HAD MARKERS AND SUBSETS OF CELLS. WE GENERATED MANY LINES OF MICE, THEY ARE EXTREMELY SUCCESSFULLY IN MANY EXPERIMENTS. AND WE WEREN'T GENERATING LIVES OF MICE THAT NEEDED TO BE CREATED WITH THE SAME RATE AND SAME REASONS. SO WE DECLARED QUICKRY AND NO LONGER FUNDING KEY I DIDN'T SAY OF THOSE MICE AND ARE USING THE MONEY IN A DIFFERENT FASHION. SO WE HAD A GOAL REACHED THE GOAL AND WE HAD A SUCCESSFUL PROGRAM. NOT SO SUCCESSFUL STORY IS CLINICAL RESEARCH CONSORTIUM, CREATED TO ADDRESS THE PROBLEM OF RECRUITMENT OF PATIENTS INTO TRIALS. OUR L TRIALS ARE BIG, AND REQUIRE PATIENTS. THE PERIOD IS LONG. SO A MAJOR FACTOR THAT WOULD HAVE IMPROVED THE ABILITY TO CONDUCT CLINICAL TRIALS WAS TO RECRUIT MORE QUICKLY. WE CAN UNCREASE THE RATE CONDUCTING OUR TRIAL IT TURNEDDED OUT, PRIVATE PRACTITIONERS AREN'T NECESSARILY INTERESTED. WE WEREN'T PAYING THEM ENOUGH AND MANY OF OUR TRIALS WERE TOO COMPLICATED. WE ASSESSED THE FOUR YEAR MARK A RECORD FOR US. DECIDED IT WASN'T -- IT WAS A WORTHY GOAL BUT THE STRATEGY WE USED TO REACH IT WAS NEVER GOING TO GET US THERE. SO WE CLOSED DOWN AND INSTEAD INVESTED IN RECRUITMENT THANK YOU ACADEMIC CENTERS AND REGULAR SITES IN OUR TRIALS AN HAVE BEEN ABLE TO PUT IN PLACE BENCHMARKS AND REQUIREMENTS AND ACTUALLY WE HAVE MANAGED TO SOLVE THE PROBLEM IN A RATHER DIFFERENT AND CHEAPER FASHION. SO BY LOOKING AT SPECIFIC PROGRAMS, WE HAVE MADE IN ROADS. IF YOU ASK ME WHAT I WOULD CONSIDER TO BE A REAL SUCCESS, A TREATMENT THAT'S STOP REGRESSION OF ONE OF OUR DEVASTATING DISEASES, GOAL AND UNLIKELY ONE TO REACH IN THE NEXT FIVE YEARS, SOME MAY REMEMBER A PREVIOUS DIRECTOR WE HAVE TREATMENT FOR PARKINSON, SLOW PROGRESSION IN FIVE TO TEN YEARS, EVERYONEING IFS ABOUT THE TEN YEARS. FOR THIS CONVERSATION, IT'S VERY CLEAR THE PEOPLE WHO HAVE WORKED TOGETHER TO PUT -- WORK TOGETHER TO COME UP WITH THE RECOMMENDATIONS HAVE DONE A SPECTACULAR JOB OF GENERATING A VERY LONG LIST OF IMPORTANT QUESTIONS AND STRATEGIES THAT WOULD MOVE THE FIELD FORWARD MORE QUICKLY THAN IT HAS BEEN. GIVEN CURRENT FUNDING WE'RE ONLY ABLE TO ADDRESS A SUBSET OF THESE RECOMMENDATIONS, WITH INITIATIVES. THAT'S NOT TO SAY THE RESEARCH IMMUNITY WON'T ON THEIR OWN RECOMMENDATIONS AND SAY THAT IS A SPECTACULAR IDEA, I'LL WRITE A GRANT AND GET FUND AND WE WOULD MANAGE TO DO THAT WITH THAT SET ASIDE MONEY. WE HAVE TO LOOK AT HIGHEST RECOMMENDATIONS AND SEEK TO WORK TOWARDS ADDRESSING AS MANY OF THEM AS WE CAN. IF WE TWO BECOME AND LOOK AT THE 2005 PARKINSON'S MEETING, WE MADE QUITE A BIT OF PROGRESS ON MANY ISSUES HIGH PRIORITY. AND I WOULD SAY ONE IN PARTICULAR WHERE I THINK THERE'S EXTRAORDINARY PROGRESS GENETICS. WE KEEP TRACK, THERE WILL BE A REPORT CARD >> BERNARD, ARE YOU ON THE PHONE? >> YES. >> DO YOU WANT TO TRY TO ADDRESS THESE QUESTIONS AND ISSUE FROM AN INDUSTRY PERSPECTIVE FOR US? >> SURE. FIRST THANKS FOR INVITING ME. CAN YOU HEAR ME OKAY? >> YOU HAVE TO SPEAK -- >> LET ME KNOW WHEN YOU CAN HEAR ME. >> KEEP GOING. >> >> I'M YELLING. >> GOOD. SO FIRST THANKS FOR INVITING ME TO PARTICIPATE IN THE PANEL. MAYBE I COULD GIVE YOU PERSPECTIVE BY WAY OF A LITTLE BIT OF BACKGROUND. SO I'M A NEUROLOGIST AND SPECIALIZE IN PARKINSON'S MOVEMENT DISORDERS. AND I OUT OF TRAINING CAME TO NINDS WHERE WORKED WITH STORY AND OTHERS IN THE EXTRAMURAL BRANCH AS WELL AS INTRAMURAL WITH FOCUS ON PARKINSON'S MOVEMENT DISORDERS. AFTER THAT I WORKED IN ACADEMIC SETTING CLINICAL RESEARCH PROGRAM FOCUSING ON PARKINSON'S HUNTINGTON'S AND OTHER MOVEMENT DISORDERS. S IN LA FEW YEARS I MOVEED TO BIOTECHNOLOGY COMPANY CALLED BIOGEN IDEK AND ALSO BEEN VERY INVOLVED WITH FOX FOUNDATION ACTUALLY CLOSE TO INCEPTION. SO I HAVE SENSE OF PERSPECTIVE OF HOW THESE DIFFERENT ORGANIZATIONS WORK IN TERMS OF BOTH MOTIVATION AND TRACKING SUCCESS AND DEFINE SUCCESS. ONE OF THE THINGS THAT HAS SURPRISED ME THE MOST THAT MOTIVATIONS ACROSS THESE ORGANIZES ARE VERY SIMILAR ONE COUNT OR MORE SIGNIFICANTLY EFFECTIVE AND ADDRESSES OUTCOMES IN A BETTER OR DIFFERENT WAY. THE MOTIVATIONAL, I THINK IT'S QUITE SIMILAR ACROSS THE BOARD, DELIGHTED TO SEE WHEN I JOINED BIOTECH COMPANY, LEVEL OF DEVOTION AND MOTIVATION TOWARD MAKING A SIGNIFICANT DENT IN PARKINSON'S DISEASE IMPROVING TREATMENT IS QUITE INTENSE WE HAVE THE EASIEST IN SOME WAYS INDUSTRY, THAT'S BECAUSE WHEN YOU LOOK AT THE SPECTRUM OF RESEARCH, WE ARE AT THE MOST APPLIED. SO IT'S EASIER TO OPERATIONALLY DEFINE SUCCESS, AGAIN, THE ULTIMATE SUCCESS IS TO BRING A NEW TREATMENT TO PATIENT BUT ALONG THE WAY WE HAVE PRETTY CLEAR INFECTION POINTS AND DECISION POINTS FOR ANY PARTICULAR MOLECULE. AS A FOR EXAMPLE, JUST LOOKING AT THE TOXICITY AND SAFETY OF A MOLECULE, WHETHER OR NOT IT HAS PROPERTIES THAT ARE FAVORABLE ENOUGH TO MAKE THE TRANSITION FROM PRE-L CLINICAL TO A CLINICAL SETTING AND FIRST IN HUMAN TESTING IS A KEY PIVOTAL POINT. WE HAVE SEVERAL KEY POINTS ALONG THE WAY LOOKING AT BOY LOGIC HAS WORKED. AND ULTIMATELY PHASE 3 TRIALS PIVOTAL STUDIES. SO WE HAVE VERY CLEAR METRICS AND I THINK IT MAKES IT EASIER TO DEFINE SUCCESS ALONG THE WAY. PART OF THE REASON THOUGH THAT I THINK IN ADDITION TO TYPE OF RESEARCH WE DO, THERE ARE ORGANIZATIONAL FEATURES THAT MAKE SOME OF THESE GOALS AN MEASUREMENTS EASIER THAN IN A MORE BASIC SETTING OR BIGGER RESEARCH PORTFOLIO SUCH AS NIH. WE HAVE A FAIRLY DEFINED SCOPE, WORK IN A CLOSE SYSTEM WITH A FEW PROGRAMS WE HAVE A FINITE NUMBER OF PROGRAMS TO KEEP TRACK OF. SIMILAR ME TRICKS BECAUSE THEY'RE ALL THERAPY DEVELOPMENT PROGRAM. THE OTHER FACT TORQUE WE SPEND A TREMENDOUS AM OF TIME COMING UP WITH PRECISE DEFINITIONS, AND OPERATIONAL DEFINITION OF WHAT A PARTICULAR GOAL LOOKS LIKE FAR MORE THAN I HAVE DONE IN ANY OTHER SETTING. ONE OF THE REASONS WE DO THAT, IS BECAUSE IN AN INDUSTRY SETTING, THOSE GOALS ARE ACTUALLY REALLY USEFUL AT GETTING A TEAM ON THE SAME PAGE, CLARIFYING WHAT ALL THE DIFFERENT PEOPLE INVOLVED IN THAT PARTICULAR DRUG DEVELOPMENT PROGRAM ARE WORKING TOWARDS I FOUND IT MOST DIFFERENT AND COMPELLING THAT WORKS WELL TO GET EVERYBODY WORKING IN THE SAME DIRECTION. AND IN INDUSTRY SETTING THE GOALS ARE SHARED BY A TEAM AND THE TEAM IS REWARDED BASED ON SUCCESS OTHER FAILURE OF METRICS. IT'S HARDER IN THE GRANT SETTING WHERE IT'S MORE INDIVIDUALLY BASED RECOGNITION. I THINK IT'S A REAL KEY ORGANIZATIONAL ISSUE THAT MAKES INDUSTRY DIFFERENT FROM THE OTHER SETTING. THE OTHER MORE GENERAL THING I WANT TO WHILE GOATS ARE EFFECTIVE AND METRICS ARE EFFECTIVE IN A MID SETTING. -- APPLIED SETTING, I WOULD BE CONCERNED AS WELL ABOUT APPLYING SOME OF THESE METRICS MORE BASIC RESEARCH AND THAT IT HAS TO BE A TWO WAY STREET, WE'RE SEEING METRICS ACROSS THE HEALTHCARE SYSTEM AND IT'S CLEAR THAT THERE ARE PERVERSE INCENTIVES AT BOTH HEALTHCARE DELIVERY LEVEL AS WELL AS OTHER LEVELS INTRODUCE THESE THINGS. SO IT HAS TO BE TWO WAY STREET TO APPLY METRICS MORE PAY SICK RESEARCH A KEY COMPONENT IS REALLY THE LONG TIME HORIZON FOR REAL BREAK THROUGHS WITH NEW THERAPY. WE HAVE SEEN IT IN INDUSTRY THAT THE ANSWER WHEN YOU DON'T HAVE THE SUCCESSES YOU WANT IS TO REORGANIZE AND TRY TO MEASURE THINGS IN A DIFFERENT WAY, WHEN THE LIMITATIONS ARE OFTEN MORE BASIC FUNDAMENTAL SCIENTIFIC METRICS IN TIME AND ENERGY ON TRACKING THEM DETRACT FROM THE ACTUAL RESEARCH ENTERPRISE ITSELF. SO I THINK CLEARLY ANN RECOGNIZEED THAT IN OPENING REMARKS BUT THESE METRICS ARE SUCCESSFUL IN DIFFERENT STAKES OF RESEARCH. >> THANK YOU. TODD, YOU WANT TO TALK ABOUT THIS FROM THE (INAUDIBLE) AND ADD MAYBE ON YOURS. I KNOW THE FOX FOUNDATION THAT HAS ESTABLISHED A FEW COLLABORATIVE EFFORTS WITH INDUSTRY WHERE IN THEORY THE SHORT TERM GOALS MIGHT BE DIFFERENT THAN SHORT TERM GOALS FROM INDUSTRY. AND HOW YOU HAVE BEEN ABLE TO MANEUVER THOSE DIFFERENT NEEDS. >> SURE. AMY, THANKS FOR INCLUDING ME, THANKS FOR MAKING ME GO LAST SO EVERYONE TOOK HALF MY NOTES ALREADY. SO HIGHEST LEVEL ONE QUESTION YOU ASKED WAS WHO ARE WE ACCOUNTABLE FOR SUCCESS AND EVERYONE MENTIONED THE IMPORTANT ROLE OF THE PATIENTS AND THEIR FAMILIES COUNTING TO DELIVER NEW TREATMENTS. THAT'S WHERE THE MAJORITY OF THE FUNDING COMES FROM, EVERY YEAR WE GO BACK TO THAT AUDIENCE TO EXPLAIN WHERE THE MONEY WEPT AND WHAT THE ACCOMPLISHMENTS MADE DURING THE COURSE OF THAT YEAR. IT WAS HELPFUL HOW DAVID LAID OUT SUCCESS, THE ULTIMATE SUCCESS WE ALL WANT, NEW TRIALS PARTICULARLY DISEASE MODIFYING TREATMENTS WE ALL HAVE, AND ONE CHALLENGE WE FACE IN THE FIELD IN TERMS OF METRICS IS ASSESSING THE SUCCESSES ALONG THE WAY. IF WE WAIT TO MEASURE DOING TREATMENT IT'S OBVIOUS THAT WE HAVE REACHED SUCCESS BUT WE DIDN'T KNOW WE WERE ON THE RIGHT POINT. SO THAT IS THE CHALLENGE, I HAVE BEEN CHARGED WITH THIS NUMBER OF YEARS FOUNDATION TO COME UP WITH WAYS TO MEASURE AND ASSESS METRICS. ONE THING I LEARNED IS DESPITE ALL OF OUR HOPES AN INTENTIONS OF BEING QUANTITY THEY ACTIVE AND SCIENTISTS GRAPHS TO SHOW IN 2006 THIS PERCENTAGE OF GRANTS WERE QUOTE UNQUOTE SUCCESSFUL, IT DOES WORK THAT WAY IN COMING UP WITH A SCORING SYSTEM CAN BE MISLEADING. AS WELL AS SETTING UP METRICS YOU WANT TO BE VERY CAREFUL BECAUSE YOU CAN CREATE AN ENVIRONMENT TO DRIVE TOWARD METRIC SWISS THE POINT BERNARD WAS MAKING. I WANT TO PUT 12 DRUGS IN CLINICAL TRIALS IN 2014 AND I WILL GUARANTEE I CAN BE SUCCESSFUL, NONE OF THOSE DESERVE TO BE IN A CLINICAL TRIAL. SO I THINK AS A REAL IMPORTANT CHALLENGE IN TERMS OF SETTING UP THE METRICS. WHEN YOU LOOK AT THE HOLISTIC FIELD GREATEST CHANCE OF SUCCESS WITH LIMITED RESOURCES. ANOTHER POINT BEFORE I GO INTO CONSORTIUM, ONE POINT STORY 4a DON'T THINK IS DONE IN THE RESEARCH ARENA, IS ESTABLISHING A CLEAR GOAL AT THE START OF THE RESEARCH PROJECT. IT MAKES IT NEARLY IMPOSSIBLE TO ASSESS WHETHER YOU WERE SUCCESSFUL OR NOT IF IT'S NOT CLEAR WHEN YOU STARTED THE PROJECT WHAT YOU'RE AIMING TO ACHIEVE. AND I DO THINK THAT CAN APPLY ACROSS THE WHOLE SPECTRUM OF THE RESEARCH ENTERPRISE, DOESN'T ONLY HAVE TO BE IN THE TRANSLATIONAL STAGES. LIKE BERNARD STATED BUT THEY MIGHT BE DEFINED DIFFERENTLY IN TERMS OF THE GOAL. IT MIGHT BE MORE OPEN ENDED GOAL OR NOT AS CLEARLY STEP WISE IS IN THE CLINICAL TRANSLATIONAL SPACE BUT IS STILL NECESSARY TO ASSESS WHETHER YOU'RE SUCCESSFUL, ONE LAST POINT THE TO MAKE IS ALSO MAKING BOTH POSITIVE AND NEGATIVE RESULTS. SHARE EQUAL BARRIER OR EQUAL STAGE IN TERMS OF SUCCESS. WHERE WE ARE RIGHT NOW AND PARKINSON'S DISEASE TRYING TO MUDDLE THROUGH THE VARIOUS HYPOTHESES DISCUSSED TODAY THAT COULD LEAD TO ULTIMATE TREATMENT. WE HAVE LIMITED RESOURCES, WELL DESIGNED STUDY PROJECT THAT TAKES ONE OF THOSE APPROACHES OFFLINE ALLOWS US TO DIVERT MORE RESOURCES AND OTHER AREAS. SO BIOMARKERS, PRE-CLINICAL TOOLS AND BRIDGING THE GAP BETWEEN ACADEMIA AND INDUSTRY TO GET BOTH GROUPS TO PARTICIPATE FOR THOSE GOALS. AND THE ACADEMIC SIDE IS REALLY INNOVATIVE RESEARCH AND MEETING THEIR INCENTIVES IN TERMS OF PUBLICATION AND REPUTATION. AND INDUSTRY SIDE IS PROVIDING A FORUM WHERE THEY CAN GET ANSWERS TO THESE CRITICAL QUESTIONS AROUND THE TARGETS LIKE JOHN MENTIONEDDED IN THE EARLIER STAGES WITHOUT THE LEG WORK THEMSELVES BUILDING TOGETHER SO THAT WORKS IN SOME AREAS WHERE IT'S FUNDAMENTAL TO THE DISEASE AND PRE-COMPETITIVE VERSUS THE COMPETITIVE PART, NO COLLABORATION AND PEOPLE RACING AS FAST AS THEY CAN TO GET DRUGS ON MARKET. >> THANK YOU, BEFORE WE TURN OVER TO QUESTIONS, ANN IS OUR GUEST IN THE COMMUNITY TODAY. IF YOU HAVE ANY COMMENTS ON WHAT YOU HAVE HEARD, SPECIFICALLY I WOULD ASK IN TERMS OF WHAT YOU PRESENTED FOR THE AAMC INITIATIVE, LOOK DOUG DOWN THE ROAD WHERE WE ARE DATA COLLECTED TO ADDRESS ALLOCATION, I UNDERSTAND YOUR HESITATION ABOUT THAT, ANALYSIS ACCOUNTABILITY AND ADVOCACY. HOW DOES THE WORLD LOOK DIFFERENT NOW IN TERMS OF DISEASE SPECIFIC COMMUNITY LIKE OURS? AND WE'RE LOOKING AT INITIATIVES, THIS WORKSHOP EFFORT WILL BE IMPLEMENTED PRESUMABLY WITH A COMBINATION OF SOME NIH SET ASIDES FOR PARTICULAR PRIORITY AREAS. A LOT ON A HOPE THAT RESEARCHERS WILL PRESENT GRANT APPLICATIONS TO FULFILL THESE, HOW WILL THE WORLD LOOK DIFFERENT? SMALL QUESTION. >> THINKING HOW THE WORLD -- DIFFERENT, I WANT TO WRAP AROUND SOME OF THE COMMENTS MADE FROM THE PANELISTS, FIRST RECOGNIZING THAT THE DIFFERENT CHALLENGE BUSINESS THE SETTING RESEARCH HAS DONE WITH THE UNDERSTANDING THAT WITHOUT FUNDAMENTAL DISCOVERY WE DO HAVE NOTHING TO TRANSLATE. FOUR POINTS GO INTO THIS, THINKING HOW THE WORLD WOULD LOOK DIFFERENT FOR THE PARKINSON'S COMMUNITY BUT OTHERS AS WELL. AND THAT IS THAT WHILE WE APPRECIATE THE TIME LAG, I SHOULD SAY THAT WE HEARD THE SAME CONCERN ABOUT THE COMMUNITY BASED PARTICIPATORY RESEARCH COMMUNITY, THE APPRECIATION AT THE TIME LAG PROBABLY CANNOT BE SHORTENED THAT MUCH. SO BUT THAT MEANS WE CAN'T THINK WE'RE GOING TO DO AN EVALUATION EVERY 17 OR 25 YEARS BY LOOKING IN THE REAR-VIEW MIRROR SO THERE HAS TO BE SUCCESS ALONG THE WAY. DAVID MADE THAT POINT. THE SECOND POINT THAT TODD MADE WAS THAT WE HAVE TO THINK ABOUT ESTABLISHING A CLEAR GOAL FOR EVALUATION AND SUCCESS AT THE START. IN THOSE METRICS, LET'S NOT CONFUSE POSITIVE RESULTS AND NEGATIVE RESULTS WITH SUCCESSES AND FAILURES. LET'S VIEW THE METRIC THAT A NEGATIVE RESULT IS A LEARNING EXPERIENCE AND NOT FAILURE. SO WE HAVE TO VEER AWAY FROM SAYING POSITIVE RESULTS AND NEGATIVE RESULTS BECAUSE I THINK IT PUTS A DIFFERENT CONNOTATION IN THAT WE ARE LEARNING FROM THE NEGATIVE RESULT AS WELL AND THAT HAS TO BE PART OF THE EVALUATION. SYSTEM. FINALLY, THIS NOTION OF PRE-COMPETITIVE SPACE I'M OFTEN STRUCK BY THE DIFFERENCES AND YET SIMILARITIES. I THINK UNDERSTANDING EVALUATION IN TERMS OF BRINGING TOGETHER INDIVIDUALS FROM THE BASIC SCIENCE COMMUNITY FROM FUNDERS FROM NIH AND FROM THE CLINICAL SCIENCE COMMUNITY, HAS TO BE PART OF ENGAGING IN THOSE METRICS. SO WHAT WOULD I SEE LOOKING FORWARD? IF THIS WERE ALL TO COME ABOUT, WHAT WOULD BE SUCCESS, I THINK YOU WOULD SEE CONTINUED SUCCESS ALONG THE SPECTRUM FROM FUNDAMENTAL DISCOVERY TO PATIENT SATISFACTION AND FEELING RESPECTED BY THE RESEARCH IMMUNITY, THAT'S HUGE AND THERE'S METRICS TO MEASURE THAT. I DON'T THINK STORY WILL MAKE THE MUSTANG SAYING WE'RE GOING TO HAVE A TREATMENT ADVANCE OR A CURE FROM SOMETHING. IN THE NEXT HOWEVER MANY YEARS. THAT'S WHAT WE WANT TO GET AWAY FROM. ON THE OTHER HAND WE HAVE TO USE LANGUAGE THEY UNDERSTAND, THEY KNOW A LOT ABOUT DYSFUNCTIONAL MITOCHONDRIA THE WAY THE LYSOSOMES TAKE CARE. THEY KNOW A LOT ABOUT PARKINSON AND OTHER NETWORK. WHAT THEY WANT TO KNOW IS ALONG THOSE PATHWAYS ONE OF THESE INCREMENTAL MARKERS OF SUCCESS THAT GIVE US HOPE FOR THE FUTURE. I THINK THAT'S WHAT I THINK THE TRUE SUCCESS OF ANY EVALUATION IS HOW MUCH HAVE YOU IMPROVED THE REALITY TOWARD THE HOPE FOR THE FUTURE, IN THIS CASE FOR PARKINSON'S. >> IF THERE IS A BURNING QUESTION OR COMMENT WE WILL BUT OTHERWISE BETH ANN AND STORY WANT TO KEEP THIS DAY ON SCHEDULE SO WE HAVE COME TO OUR CLOSING TIME. ALL RIGHT. WITH THAT I THANK OUR PANELISTS AND BERNARD THANK YOU VERY MUCH. I HOPE YOU ARE WARM AND DRY. [APPLAUSE]