>> GOOD AFTERNOON AND WELCOME TO CLINICAL CENTER GRAND ROUNDS, TODAY WE HAVE TWO WEEKERS FOCUS ON THE TOPIC MAGNETIC RESONANCE IMAGAGE AND BRAIN IMAGING AND BIOMARKERS AND IMPLICATIONS TO THERAPY. SPEAKING FIRST DR. RAMONE DIAZ-ARRISTA, DIRECTOR OF THE CLINICAL RESEARCH, CENTER FOR NEUROSCIENCE AND REGENRATIVE MEDICINE, AND PROFESSOR OF NEUROLOGY AT THE UNIFORM SERVICED UNIVERSITY OF THE HEALTH SCIENCES. AND SPEAKING SECOND AND DR. LAWRENCE L. LATTOUR, AND AND PRINCIPLE INVESTIGATOR AND THE DIAGNOSTIC IMAGING PROGRAM AND REGENRATIVE ANSWER, AND TWO REPRESENT A PARTNERSHIP BETWEEN NIH AND THE DEPARTMENT OF DEFENSE, ALL OF US ARE VERY EXCITED ABOUT. DR. DIAZ ARISTA IS A GRADUATE OF GRADUATE UNIVERSITY, EARNED Ph.D. IN BIOCHEMIST RADIOY AND AN MD DEGREE AT THE BAYLOR COLLEGE OF MEDICINE, HE COMPLETED AN INTERNSHIP IN INTERNAL MEDICINE ISRAEL MEDICAL CENTER TEACHING HOSPITAL OF HARVARD, RESIDENCY OF NEUROLOGY AT THE COLUMBIA PRESBYTERIAN MEDICAL CENTER IN NEW YORK. HE SERVED AS A MEMBER OF THE INSTITUTE OF MEDICINE'S COMMITTEES ON PUBLIC HEALTH DIMENSIONS, THE EPILEPSYS AND TRAUMATIC BRAIN INJURY, HIS MEMBERSHIPS INCLUDE THE SOCIETY OF NEUROSCIENCES AND THE AMERICAN ACADEMY OF NEUROLOGY, AND EDITORIAL BOARD OF NEURAL TRAUMA AND HIS SPECIAL TOPICS EDITOR OF THE TRAUMA REHABILITATION AND UNDERSTANDING OF MOLECULAR CELLULAR TISSUE MECHANISM AND SECONDARY NEURONAL INJURY AND NEUROREGENERATION, AND HIS RESEARCH IS PRIMARY ILLEGALSY INVOLVED HUMANS, WITH TRAUMATIC BRAIN INJURIES AND CHRONIC STAGES. AND DR. LA TOUR EARNED A BS IN ELECTRICAL ENGINEERING AND Ph.D. IN BIOMEDICAL ENGINEERING AT THE POLYTECH INSTITUTE WHERE HE COMPLETED POST DOCTORAL FELLOWSHIP AND ALSO COMPLETED THE DEPARTMENT OF ENERGY ALEXANDER HOLLANDER POST DOCTORAL FELLOWSHIP AT BROOK HAVEN NATIONAL LABORATORIES IN NEW YORK AND CAME TO THE NIH POSITION IN NEW YORK IN 2000 THE INTERROGATIONAL SOCIETY OF MAGNETIC RESIDENCE IN MEDICINE AND HIS RESEARCH IS ON THE USE OF NEUROIMAGING, TO CHARACTERIZE PATIENTS WITH ACUTE STROKE AND TRAUMATIC BRAIN INJURY AND HE FOCUSES ON METHODS TO IDENTIFY AND STUDY THE EVOLUTION OF POTENTIAL THERAPEUTIC TARGETS. NOW, PLEASE WELCOME DR. DIAZ-ARRISTA! >> WELL THANK YOU SO MUCH FOR THE KIND INVITATION AND SPEAKING HERE AND I'M HONORED TO BE HERE AND SINCE MOVING TO BETHESDA FRIENDSHIPS AND COLLABORATIONS THAT WE HAVEN'T BEEN ABLE TO SET UP, THESE ARE MY DISCLOSURES: I HAVE NO RELEVANT FINANCIAL RELATIONSHIPS TO WHAT WE'RE TALKING ABOUT TODAY AND THIS IS AN OUTLINE WHAT I'M PRESENTING AND I WILL SPEPPED TIME ON, AND HAS HISTORICALLY BEEN THE POOR STEP CHILD, AND AND IT'S WORTH SPENDING A LITTLEIT OF TIME TALKING ABOUT HISTORY, EPIDEMIOLOGY AND HISTORY OF PRIOR ATTEMPTING AT COMING UP WITH THERAPIES AND TRAUMATIC BRAIN INJURY, AND THEN I WILL TALK ABOUT WORK WE HAVE MAINLY DONE IN DALLAS WITH MY RESEARCH GROUP THERE OVER THE LAST 10 YEARS OR SO, WHICH REALLY KIND OF FRAME THE PICTURE FOR WHAT WE'RE GOING TO BE DOING OVER THE NEXT SEVERAL YEARS AND UNDERSTANDING HOW MRI, APPEARS TO BE A VERY USEFUL TOOL TO IDENTIFY BIOMARKERS OF TRAUMATIC BRAIN INJURY THAT WILL BE USEFUL FOR DEVELOPING THERAPIES AND AT THE END TALKING ABOUT TWO CLINICAL TRIALS THAT ARE UNDER DEVELOPMENT, RELATIVELY FAR ALONG BUT STILL UNDER DEVELOPMENTS SINCE MOVING HERE IN JULY, I HAVE BEEN TAKING A GRADUATE COURSE, POST GRADUATE COURSE IN THE FEDERAL BEOCRACY WHICH HAS LED TO THESE TWO THINGS, BEING UNDERWAY, BUT WE'RE VERY EXCITED ABOUT GETTING THESE THINGS GOING, CERTAINLY IN THE NEXT SEVERAL MONTHS. POLITICAL ME START OFF WITH HISTORY AND I WANT TO MAKE THE POINT THAT TRAUMATIC BRAIN INJURY, HAS BEEN AN INTIMATE COMPANIONS WITH PEOPLE THROUGHOUT HISTORY AND EVOLUTION AND BEFORE WE WERE HUMANS THERE'S EVIDENCE FROM A SOUTH AFRICAN SKELETON, THIS IS A PREHUMAN ANCESTOR, HAD EVIDENCE OF CRANIAL FRACTURES FROM AN ACULT OF AN ANTILOPE, SO IT'S PRETTY CLEAR ONE OF THE FIRST THINGS WE DID DURING OUR EVOLUTION, VERY SOON AFTER DISCOVER TAG WE HAD OPPOSABLE THUMBS WAS TO USE THAT TO CLUB A CLUB AND BARB ANOTHER HUMAN IN THE HEAD WITH, IN FACT, THE EDWIN SMITH SURGICAL PAPEROUS, EARLIEST MEDICAL TEXT CLEARLY DRIBS TRAUMATIC BRAIN INJURYS AND THE CONSEQUENCES OF THAT RESULTED FROM HEAD INJURY. NOW QUANTITATIVELY THERE'S BEEN RECENTLY VERY NICE STUDIES IN PHYSICAL ANTHROPOLOGY WHICH INDICATES THAT TBI, WAS PROBABLY AN IMPORTANT FACTOR DURING THE EVOLUTION OF THE BRAIN AND A SELECTIVE FACTOR DURING HUMAN EVOLUTION, SO WHAT THESE STUDY VS DONE AND HAVE LOOKED AT THESE ARE PRESENCE IN THE BURIAL SITES AND LOOKED FOR THE PRESENCE OF HEALED OR UNHEALED SKULL FRACTURES AND WHAT CAN YOU SEE IS THAT SOMEWHERE IN THE NEIGHBORHOOD OF 20-30% OF OUR ANCESTORS DURING PREHISTORIC, EVOLUTIONARY TIME SUFFERED SIGNIFICANT TRAUMATIC BRAIN INJURIES, THINGS IN MOST CASES THEY SURVIVE, WHICH I THINK IMPLIES THAT ANY GENETIC FACTORS OR ANY GENE VARIANCE THAT WOULD HAVE PREDISPOSED TO EITHER RESISTANCE FROM TRAUMATIC BRAIN INJURY WOULD HAVE FACILITATED BRAIN INJURY FOR PROBABLY FACTORS THAT WERE SELECTED DURING EVOLUTION, AND IF WE'RE EVERY SMART ENOUGH TO FIND OUT WHAT THOSE FACTORS ARE AND WE WOULD BE AHEAD OF THE GAME. BIG PROBLEM IN MODERN SOCIETIES, NOT AS BIG A PROBLEM IN PREHISTORY, BUT IN THE UNITED STATES, THERE ARE APPROXIMATELY TWO MILLION MERGE DEPARTMENT VISITS EVERY YEAR FROM TRAUMATIC BRAIN INJURY AND THE VAST MAIORITY OF THOSE ARE MEALED AND THERE'S SOMEWHERE IN THE ORDER OF 300,000 OR SO HOSPITAL ADMISSIONS FROM TRAUMATIC BRAIN INJURY OR SO, 50,000 FATALITIES, AND BECAUSE THIS IS A PRIMARILY A DISEASE OF YOUNG PEOPLE WHO LIVE FOR YEARS AND IN MOST CASES THERE'S MODERN SURGICAL TECHNIQUES AND MODERN NEUROINTENSIVE CARE, SURVIVAL IS VERY, VERY, HIGH, APPROXIMATELY FIVE MILLION AMERICANS, LIVE WITH DISABILITIES THAT WERE PRODUCED WITH TRAUMATIC BRAIN INJURIES SO THIS IS ROUGHLY TWO% OF THE POPULATION AND TBI IS IN FACT, THE MOST COMMON CAUSE OF DEATH OR PERMANENT DISABILITY IN PEOPLE UNDER THE AGE OF 45. NOW IT'S TRUE THAT MOST PEOPLE IN THE AGE OF 45 ARE VERY HEALTHY WHICH IS WHY TBI IS AN IMPORTANT PROBLEM AND THIS IS THE MOSTN'T PHASE OF LIFE, SO YOUNG PEOPLE THIS IS A TIME WHEN WE'RE COMPLETING EDUCATION, WHEN WE ARE STARTING OUR FAMILIES, CREATING OUR INTERPERSONAL RELATIONSHIPS GETTING YOUR VOCATIONAL LIFE IN ORDERED SO IN THIS MOST CRITICAL PERIOD OF LIFE, TRAUMATIC BRAIN INJURY IS THE MAJOR CAUSE WITH DEATH AND DISABILITY WITH A VERY, VERY HIGH COST TO SOCIETY. THIS IS A BIG PROBLEM IN THE MILITARY AS WELL. I NOW WORK WITHIN THE MILITARY INSTITUTION AND AS EXPECTED WE GET YOUNG PEOPLE AND WE SEND THEM OFF TO WAR AND EACH WITH WE DON'T SEABED THEM OFF TO WAR, WE SEND THEM OFF TO TRAINING AND JUMPING OUT OF AIRPLANES AND TRENCHES, ET CETERA, TBI IS A MAJOR PROBLEM THERE, SO THIS IS FROM THE BRAIN INJURY CENTER INDICATING NUMBER OF BRAIN INJURIES OVER THE LAST 10 YEARS AND I WANT TO POINT OUT A FEW MORE THINGS, AND THE OTHER THING I WANT TO POINT OUT IS THAT THE WAR STARTED RIGHT AROUND HERE AND IN FACT IT REALLY GOT GOING, ABOUT HERE, BUT EVEN IN PEACE TIME, THE MILITARY MEDICAL SYSTEM, AND YOUNG MEN IN WOMEN AND UNIFORM ARE AT RISK OF A SIGNIFICANT HEAD INJURIES JUST FROM THE FACT THEY'RE YOUNG PEOPLE BUT ALSO THE FACT THAT THEY DO IS PART OF THEIR JOB IN TERMS OF TRAINING, ET CETERA. THIS CAUGHT THE MEDICAL SYSTEM BY SURPRISE BECAUSE SINCE THE MILITARY ARMOR BETTER AND REDUCTION IN MORTALITY AND IMPROVEMENT IN SURVIVAL AND REDUCTION IN SEVERE INJURIES AND CURRENT MILITARY SETTING, THIS HOWEVER CAUGHT EVERYBODY BY SURPRISE, BECAUSE WE'RE NOW PAYING ATTENTION TO THEM, AND THE CONCERN WAS THAT THIS IS A NEW TYPE OF INJURY, SOMETHING THAT HAD NEVER BEEN SEEN BEFORE, I'M NOT SURE THAT'S TRUE, I THINK TBI IS SOMETHING THAT HAS BEEN THE CASE IN EVERY CONFLICT, PROBABLY GOING TO BACK WHEN WE WERE IN THE CAVES AND MILD TBI IS PART OF EVERY CONFLICT AS WELL AND NO ONE PAID ATTENTION TO IT BECAUSE THERE WERE MUCH MORE SEVERE INJURIES THAT TOOK EVERYBODY'S ATTENTION THIS, IS THE PICTURE FROM THE CURRENT CONFLICT, THIS IS THE PIBLGHTURE FROM THE BATTLE--PICTURE FROM THE BATTLE OF DIPOLLI, WORLD WAR ONE AND THIS SOLDIER IS AN AUSTRALIAN INFANTRY MAN IS DEMONSTRATING WHAT WAS CALLED AT THE TIME THE THOUSAND YARD STARE AND IT WOULD BOTTOM CALLED SHELL SHOCK. SO SHELL SHOCK WAS A TERM THAT WAS THE FIRST WAR WHERE HIGH INTENSITY WAS USED WITH WARFARE AND THE PROBLEM IS THE SERVICE MEMBERS WERE HAVING A CONSEQUENCE OF THEIR COMBAT, THIS GAME SUCH A PROBLEM IN BRITAIN IT WAS A PROBLEM EVERY WHY AND BRITAIN IT WAS TAKEN TO MOST THOROUGH INVESTIGATION, THE UNITED KINGDOM SET UP A SHELL SHOCK MISSION CALLED THE SOUTHERN COMMITTEE AND IN 191922, THEY TOOK EXPERTS AND THAT CONCLUDED THAT SHELL SHOCK IS A FORMER MA LINGERING OR COW ARDNESS THAT ARE LACKING FIBBER AND THE SHELL SHOCK WAS NOT A DISEASE IN THE TERM SHOULD BE BANNED. OBVIOUSLY, HAVING A COMMISSION SAY THAT A TERM SHOULD BE BANNED DOESN'T MEAN THAT IT WILL BECAUSE IN FACT, IT WAS DESCRIBING SOMETHING REAL THAT AND NOW WE'RE ALMOST A HUNDRED YEARS LATER AND THIS PROBLEM IS WITH US AND IT'S STILL A A QUESTION OF WHAT EXACTLY IS HAPPENING WITH THE TRAUMATIC BRAIN INJURIES THAT OCCUR DURING MILITARY SERVICE AS WELL AS A LARGE NUMBER OF THESE BRAIN INJURIES ARE CURING THROUGH CIVILIAN LIFE. SO BECAUSE OF THIS IN 2007 CONGRESS ESTABLISHED THE CNRM, WHICH WAS SPECIFICALLY DESIGNED TO BRING TOGETHER DECISIONS IN SCIENTISTS AT THE UNIFORM SERVICES UNIVERSITY, AS WELL AS NIH TO DEVELOP APPROACHES FOR BRAIN INJURY, DIAGNOSE AND THERAPY. SO IT'S A VERY NEW CENTER, BUT IT HAS GROWN RAPIDLY OVER THE LAST SEVERAL YEARS, CONGRESSIONAL ACT OF 2007, IT WAS 2008 WHEN THE MONEY WAS APPROPRIATED, 2009 THE PROJECT GOT STARTED. AS OF NOW, THERE ARE APPROXIMATELY 50 PRECLINICAL RESEARCH PROJECTS, 25 CLINICAL PROJECTS, ALMOST 300 PEOPLE WHO ARE WORKING ON CNRM PROJECTS AND NOW POETIC PUT THAT INTO PERSPECTIVES, SEVERAL YEARS AGO, I WAS INVITED TO ATTEND THE SIM OPPOSEDIUM OF THE TBI RESEARCH CENTER IN PENNSYLVANIA, WHICH WAS PROBABLY THE LARGEST ACADEMIC TBI RESEARCH CENTER, WHICH HAS BEEN AROUND SINCE THE 1970S AND THERE WERE 200 PEOPLE THERE, THERE WAS JUST A COUPLE OF YEARS, THE CNRM HAS BECOME IN THE UNITED STATES, THE LARGEST TBI RESEARCH AND CLEARLY WE DON'T HAVE DECADES OF EXPERIENCE BUT THERE'S A LOT OF IMPORTANT PROJECTS AND A LOT OF EXCITEMENT GOING ON. SO, WHAT HAS BEEN DONE IN THE FIELD WHAT HAS BEEN THE PROGRESS TO DATE AND A LOT OF WORK HAS BEEN DONE IN AND OUT OF MODELS, A LOT OF WORK IS ONGOING AND MANY OTHER PLACES AND A LOT OF DIFFERENT MODELS HAVE BEEN DEVELOPED IN RODENTS BUT ALSO IN OTHER ANIMALS, THESE ARE MODELS ESTABLISHED AT THE CNRM NOW AS WELL AS OTHER CENTERS AND THIS WORK HAS BY AND LARGE BEEN SUCCESSFUL AND THERE ARE BY NOW A LARGE NUMBER OF THERAPIES THAT IN RODENTS IN ANIMAL MODELS HAVE SHOWN EFFICACY IN REDUCING AND REPAIR, NEW AGENTS KEEP AT IT ALL THE TIME AND EVEN AT THE CNRM CLOSING LAST WEEK THERE WERE AGENTS I HAD TO ADD TO THE LIST. UNFORTUNATELY THOU, I HAVE IN ORANGE ARE DRUGS THAT ALTHOUGH THEY WORK IN ANIMALS HAVE BEEN TRIED IN CLINICAL TRIALS IN HUMANS, AND THE RESULT OF THOSE TRIALS HAVE BEEN VERY UNIFORM AND THEY HAVE ALL BEEN NEGATIVE AND POSSIBLE TO DATE TO TRANSLATE US AT WORK, ANY OF THESE THERAPIES THAT SHOW PROMISE IN THE RODENTS INTO HUMAN CLINICAL TRIALS. NOW THIS EFFORT IS NOT--IT'S STILL ONGOING, WHAT I HAVE IN BLUE ARE DRUGS THAT ARE STILL BEING TESTED, HOWEVER BEING TESTED USING THE EXPERIMENTAL DESIGN, PRETTY MUCH CONSISTENT WITH ALL THE NEGATIVE TRIALS AND WHAT WE HAVE TO THINK ABOUT IS WHAT WENT WRONG OR GONE WRONG WITH THE TRANSLATION, WHY HAVE WE HAD THIS DIFFICULT IN TRANSLATING PROMISING RESULTS FROM THE ANIMAL MODELS INTO, CLINICAL SITUATION, AND THERE ARE PROBABLY MANY REASONS FOR THAT BUT ONE OF THE MORE IMPORTANT REASONS IS THAT WE HAVE INSUFFICIENT INFORMATION ABOUT THE HETEROGENEITY OF TBI AND DON'T HAVE GOOD CLINICAL MEASURES OF PHENOTYPING MECHANISMS AND IN PARTICULAR, WE'RE GOING TO HAVE TO DO THAT. WE'RE GOING TO HAVE TO HAVE THOSE MEASURES BEFORE WE COME UP WITH DRUGS THAT ARE GOING TO BE AFFECTED BECAUSE IT'S LIKELY THAT DRUGS MAY BE EFFECTIVE IN ONE MECHANISM MAY NOT BE EFFECTIVE IN ALL OF THEM. THIS HAS BEEN A TOPIC OF DISCUSSION FOR THE LAST SEVERAL YEARS, MAY HAVE BEEN A NUMBER OF CONFERENCES THAT THE NINDS, HAS CONVENED OVER THE LAST SEVERAL YEARS AND THIS IS ONE WHERE I PARTICIPATED LARRY I BELIEVE YOU WERE PART OF THIS AS WELL, AND ONE OF THE CONCLUSIONS OF THIS CONSENSUS CONFERENCE THAT MORE WATCH OF ACUTE MRI WILL BE IMPORTANT TO PROVIDE DETAIL AND EFFORTS COORDINATED TO ELIMINATE BARRIERS FOR ORBTANNING ACUTE MRI AND TRIALS AND I THINK THIS WAS CERTAINLY TRUE IN 2007, AND CERTAINLY, EVEN MORE TRUE NOW WITH SUBSTANTIAL BETTER RESEARCH. NOW THIS IS A THIS IS A GRAPHICAL APPROACH THAT I PLAY GOOD WITH AS NEUROPATHOLOGIST AT BAYLOR AND HE WAS AT THE WORKSHOP AND SHARED WITH US A WAY TO VISUALIZE THE PROBLEM THAT WE'RE DEALING WITH, SO IN A SENSE, THERE REALLY ISN'T ANYTHING FUNDAMENTALLY DIFFERENT BETWEEN GRENADE THROUGH SEVERE DRAMATIC BRAIN INJURY OTHER THAN A MATTER OF SCALE, SO SEVERE TBI WAS LIKELY TO BE SEVERE AND THE CONE CAN REPRESENT ALL THE DIFFERENT VARIETIES OF PATIENTS THAT CAN DEVELOP TBI, AND IF YOU TAKE A CROSS SECTION OF THIS CONE, OR EACH INDIVIDUAL CROSS SECTION CAN BE VISUALIZED AS DIFFERENT ENDOPHENOTYPES OR DIFFERENT MECHANISMS THAT TOGETHER PRODUCE THE PROBLEM, SO THIS ONE INDIVIDUAL FOR EXAMPLE HERE HAS A RELATIVELY CROSS SECTION AND THAT IS A SOMEWHAT MILDER INJURY, AND EACH OF THESE VECTORS CORRELATES WITH THE MAGNITUDE OUT OF DEPARTURE FROM NORMAL SO IT'S A FAIRLY NORMAL VERY WITH A SMALL VECTOR, HE HAD A CRANEIO HEMORRHAGE THIS, IS A MERE SEVERE SITUATION SO THIS APPROACH GIVES YOU A VIEW OF HOW WE CAN CONCEPTUALIZE INJURY SEVERITY, BY LOOKING AT ALL THESE DIFFERENT ENDOPHENOTYPES. SO MRI IS ONLY ONE WAY TO IDENTIFY THOSE PHENOTYPES, I THINK ANOTHER WAY IS PHYSIOLOGIC EVALUATIONS OR BIOCHEMICAL EVALUATIONS BUT MRI HAS PARTICULAR VALUE AND THAT'S CERTAINLY WHAT THE REST OF TODAY'S TALK IS GOING TO BE ON, SO I'M GOING TO TALK ABOUT, WORK WE HAVE MAINLY DONE IN DALLAS AND IT'S STARTING TO TRANSLATE HERE. INITIALLY WE QUANTITATEIT VOLUMEETIC ASSESSMENTS WHICH I BELIEVE IS REALLY READY FOR PRIME TIME IN TERMS FOR ADAPTATION FOR MEASURES FOR HUMAN CLINICAL PRODUCT. I WILL TALK SOME OF DIFFUSION TENSE IMAGING WHICH IS A NOVEL TECHNIQUE WHICH IS PARTICULARLY USEFUL FOR IDENTIFYING EXONAL INJURY, MAYBE NOT QUITE THERE YET BUT WILL BE VERY, VERY, SOON AND THEN FINALLY I'LL TALK ABOUT THE CLEVER WAY TO MEASURE SEER EASTBOUNDERAL VASCULAR ACTIVITY IN THE MRI, BASE, AND THAT MAY BE A DISTAL WAY TO MEASURE THE EFFICACY OF DRUGS TARGETED AT VASCULAR HEALTH. SO, LET'S START WITH QUANTITATIVE VALIUMETIC ASSESS WANTS. IT'S BEEN KNOWN A LONG TIME THAT CEREBRAL ATROPHY, AND A COMMON PLACE OF TBI AND THIS IS ONE PATIENT WE TOOK CARE OF IN DALLAS, HE WAS SCANNED WITHIN A FEW DAYS OF INJURY, CAN YOU SEE FAIRLY EXTENSIVE AXONAL INJURY, YOU CAN SEE THE BODY OF THE CORPUS, AND HE CAME BACK SIX MONTHS LATER HE HAD NOT DONE WELL, DOSE OF THREE, MEANS HE WAS DEPENDENT ON OTHERS FOR PRETTY MUCH ALL OF HIS ADLs, AND THE MORE PREDOMINANT THING ABOUT THE MRI WHEN THEY'RE A COUPLE LITTLE HOLES HERE AND THERE, MOST BRIGHT ABNORMALITIES DISAPPEAR, AND THE KEY THING IS THAT THIS SCAN OF A 18 YEAR-OLD LOOKS LIKE A SCAN OF A 70 YEAR-OLD AND THERE HAS BEEN GLOBAL ATROCHE--ATROPHY AND COMPARING THE SCANS THIS MAN EXPERIENCED A LOSS OF TOTAL BRAIN VOLUME OF AROUND 10% OVER THE LAST SIX MONTHS AND TO PUT THAT IN PERSPECTIVE, A TIP KACCT PATIENT OF ALZHEIMER PATIENT HYMER SYSTEM LOSING ONE-TWO% OF BRAIN VOLUME PER YEAR SO IN SIX MONTHS THIS MAN LOST AS MUCH BRAIN AS A CONSEQUENCE OF HIS TBI, AS A TYPICAL ALZHEIM PATIENT HYMER'S PATIENTS LOSES IN FIVE TO 10 YEARS. WHAT OUR NEUROLOGY RESIDENT IN DALLAS IS ABLE TO DO IS TO LOOK AT ASSOCIATION BETWEEN THE VOLUME OF ACUTE LESIONS, IN THE SCAN DONE IN THE FIRST TWO DAYS, WITH THE CHANGE IN BRAIN VOLUME OF THE FIRST SIX MONTHS AND IN FACT THERE IS A PRETTY DESCENT RELATIONSHIP NOT PARTICULARLY THAT STRONG BUT HIGHLY SIGNIFICANT INDICATING THAT THE LESIONS THAT WE CAN MEASURE IN THE ACUTE SCAN ARE FACT MEANINGFUL BECAUSE THEY ARE HIGHLY ASSOCIATED WITH THE EVENTUAL DEGREE OF BRAIN ATROPHY THAT IS GOING TO BE SEEN WHEN THESE PATIENTS COME BACK AND OBVIOUSLY BRAIN ATROPHY IS ON ITS FACE A VERY PROMISING BIOMARKER FOR OUTCOME AND OBVIOUSLY HIGHLY ASSOCIATED WITH DISABILITY, FOLKS THAT HAVE GREATER DEGREES OF BRAIN ATROPEY, USED DISABILITY. NOW THIS IS NOT OHM A GROABAL THING IS MATT WARNER IN MY LAB, A STUDENT, DEVELOPED THIS PROGRAM, AND FREE SURFY ALLOWS YOU TO ASSESS REGIONAL BRAIN VOLUMES AND USE THAT SOFTWARE IN OUR GROUP OF MAINLY MODERATE SEVERE TBI PATIENTS HE DISCOVERED THAT THE ATROPHY THAT WAS COMMON AFTER TBI IS NOT DIFFUSE AND NOT SYMMETRICAL EVERYWHERE AND THERE'S SOME AREAS OF THE BRAIN THAT HAVE, THAT ARE PARTICULARLY SENSITIVE TO ATROPEY, WE SOMEWHAT NEW THAT BUT HADN'T DONE IT IN A PROPOSAL WAY IN THESE ISSUES, AND IN THIS PARTICULAR GROUP OF PEOPLE, OVERALL IT WAS FOUR AND HALF% IN CHANGE IN WHOLE BRAIN VOLUME OVER SIX MONTHS. THERE WAS ATROPHY BOTH IN THE WHITE MATTER AND THE GRAY MATTER, ALTHOUGH THE ATROPHY WAS MORE PRONOUNCED, THIS PARTICULAR GROUP OF PATIENTS WE SELECTED TO HAVE PRIMARILY EXONAL INJURIES SO THAT WAS NOT A SURPRISE. OBVIOUSLY THE INCREASE IN THE VENTRICLES WAS MUCH LARGER. PERCENTAGE WISE, THE VENTRICLES WILL GET LARGER, WHAT MATT FOUND WAS THAT NOT ALL STRUCTURES SHOWED ATROPHY OF THE SAME DEGREE, FACTS LIKE THE HIPPOCAMPUS, SHOWED ATROPHY ABOVE 10 TO 15% AND CAUGHT IT INTO THE CEREBELLUM AND ARE RESISTANT TO POST-TRAUMATIC INJURY, SO THIS IS THE HIPPOCAMPUS, AND IT'S A STRUCTURE THAT CAN BE MEASURED BY MANUEL TRACING AND HAD BEEN SHOWN PREVIOUSLY TO OUR WORK, THAT THE HIPPOCAMPUS WAS SOMEWHERE AROUND 10% OR SO AFTER TBI, BUT THIS WORK SHOWED CLEARLY NOT LIMITED HYPOCAMPUS MANY OTHER STRUCTURES ALSO HAD THE SPECIES SENSITIVITY BUT FREE SURFY ALSO ALLOWS TO YOU DO IS LOOK AT THICKNESS OF CORTEX IN AN UNBIASED FASHION, SIMILARLY ATROPHY IN THE CORTEX IS NOT UNIFORM IS NOT THE SAME IN EVERY STRUCTURE, AND THERE ARE CERTAIN CORTICALE REGIONS AND THAT INCLUDE THE PREKUHNIOUS, POSTERIOR SINGULET AND FRONTAL CORTEX AND OTHER REGIONS AS WELL. SO I THINK THIS TELLS YOU SOMETHING ABOUT THE BIOLOGY OR ABOUT THE PATHOPHYSIOLOGY OF WHAT'S GOING ON, BUT ATROPHY, THIS IS JUST TO SHOW THE DISATROPHY IS IN FACT MEANINGFUL AND IT'S HIGHLY ASSOCIATE WIDE DISABILITIES SO THERE'S NO ATROPHY, THE LIKELIHOOD OF ANY DISABILITY OR SEVERE DISABILITY IS QUITE LOW, IN THE MORE SEVERE CASES, WHEN ATROPHY WAS OVERALL 10% OR MORE, ALL THOSE PEOPLE HAD SOME DISABILITY AND HALF OF THEM HAD SEVERE DISABILITY. AND HAS DEVELOPED MORE REFINED METHODS TO LOOK AT THE CEREBRAL ATROPHY WHICH WILL BE REQUIRED IF WE ARE GOING TO BE STUDYING PEOPLE WITH MILDER INJURIES, METHOD THAT THAT ASSOCIATES DEVELOPED HERE AT THE NIH, OVER THE LAST YEAR OR SO, AND I THINK WHAT YOU CAN SEE, THIS IS THE INITIAL SCAN, THIS IS FOLLOW UP SCAN, THEY LOOK PRETTY DARN SIMILAR, BUT WHEN YOU USE THESE HIGH REFINED QUANTITATIVE METHODS WHAT IS READ ARE REGIONS WHERE THERE HAS BEEN ATROPHY OVER THE SIX MONTHS PERIOD WHAT HE SHOWS HERE, HIS METHOD OF USING THIS NONLINEAR REGISTRATION IS MORE SENSITIVE AND MORE ACCURATE THAN THE METHOD WE TEND TO USE WHICH IS SEGMENTATION. SO PARTICULARLY FOR MILD BRAIN INJURIES THIS IS A GOOD WAY I'M LOOKING AT IT AS LONG AS WE'RE MAKING TERRIFIC PROGRESS, AND IDENTIFYING THIS. NOW THE REASON THIS IS IMPORTANT IS BECAUSE BRAIN ATROPHY IN PARTICULAR REGIONAL BRAIN ATROPHY, IS VERY ATTRACTIVE AS A CANDIDATE SURROGATE BIOMARKER, RIGHT? THE REASON THE TBI CLINICAL TRIALS HAVE BEEN DIFFICULT TO DO IS THAT FUNCTIONAL OUTCOME AFTER TBI IS AFFECTED BY SO MANY THINGS, THAT ARE NOT DEPENDENT ON THE BIOLOGY OF THE INJURY AND THE BIOLOGY OF REPAIR, RIGHT? THEY CAN BE AFFECTED BY PREMORBID FACTORS AND FACTORS AND THE SOCIOECONOMIC OF THE FAMILY AND THEY'RE CONFOUNDERS AND THE ONLY WAY TO DEAL WITH THOSE IS TO HAVE VERY, VERY, LARGE TRIALS WHO ENROLL THOUSAND PATIENTS AND ALL THESE CONFOUNDERS ARE GOING TO WORK THEIR WAY OUT BY RANDOMIZATION, BUT THAT'S VERY, VERY, EXPENSIVE TO DO, TAKES A GREAT DEAL OF EFFORTOT OTHER HAND, BRAIN ATROPHY, PARTICULARLY REGIONAL BRAIN ATROUGH SECLOSER TO THE BIOLOGY OF THE INJURY AND THE BIOLOGY OF WHATEVER THERAPY YOU MAY WANT TO BE TESTING. SO IN THIS PARTICULAR ANALYSIS THIS, IS BASED ON OUR PILOT DATA, WE ESTIMATED THE POWER IN A STUDY OF 70 PATIENTS PER GROUP, SO THIS STUDY OF 140 PATIENTS, WHICH IS A VERY PRACTICAL SIZE STUDY THAT CAN BE DONE, SO, AT THIS--AT THIS SAMPLE SIZE, WE CAN DETECT A 20% DIFFERENCE WITHIN THE TWO GROUP FIST WE'RE USING WHOLE BRAIN VOLUME AS THE SURROGATE OUTCOME, ON THE OTHER HAND IF WE WANT TO LOOK AT REGIONS OF THE BRAIN THAT ATROPHY IS MORE PRONOUNCED IN SUCH AS HIPPOCAMPUS, THALAMUS, PREKUHNUOUS IN FACT HAVE GREATER POWER AND CAN IDENTIFY EVEN MORE SUBTLE DEGREES OF BRAIN ATROPHY AND CAN IDENTIFY MORE SUBTLE BENEFIT OF PARTICULAR THERAPY WE WANT TO USE. LET'S NOW SWITCH TO DEFUSION TENSE IMAGING THIS, IS AN EXCITING TECHNIQUE AND WAS INVENTED HERE AT THE NIH, BY DR. PREPOLI AND DR. VASKER, THAT WAS THERE AND COLLEAGUES AT OTHER PLACES, THIS IS PARTICULARLY ATTRACTIVE BECAUSE WE CAN LOOK AT AXONAL INJURY AND THAT'S BELIEVED TO BE A VERY COMMON MECHANISM, IMPORTANT MECHANISM AFTER TBI, WE HAVE LIKEWISE USED THE TECHNIQUE, TWO DAYS OF INJURY AND AGAIN SIX MONTHS OF INJURY, AND THE POINT HERE IS THAT THERE A TOTAL INJURY THAT WE DETECT ACUTELY BUT IN FACT, THE EXONAL DEGENERATION THAT GOES ON FOR SEVERAL MONTHS AFTER INJURY IS DFI SHOWS MORE OF THIS INJURY THAN YOU CAN SEE WITH THE MORE TRADITIONAL STRUCTURE, HAVE LOOKED AT DTI AND THE NUMBER OF CONDITIONS AGAIN, NUMBER OF BOXES ACUTELY IS NOT RELATED TO OUTCOME, BUT IT'S MUCH MORE THE NUMBER OF ABNORMAL BOXES IN THE CHRONIC SCAN AND EVEN MORE SO AS A FACT ONE WOULD EXPECT THERE ARE A NUMBER OF WAYS TO LOOK AT DTI DATA, ANN ATTRACTIVE WAY, YOU USED THE PROBLEM WITH ETI DATA IS YOU HAVE TOO MUCH OF IT, IF THERE IS YOU GET THE VICINITY AND YOU GET THE MANY TO ASSESS IT ALL, SOPHISTICATE STATISTIC DTRGS I IS GOOD USING THIS DISCRIP NAT ANALYSIS THAT BASICALLY USES ALL DTI DATA TOGETHER AND ABOUT 30 DIFFERENT WIDE MATTER TRACKS SOME OTHER FURTHER TOWARDS HERE WENT MORE IN THIS DIRECTION ARE THE ONES THAT DID NOT RECOVER WHILE THOSE WERE THE DTI PARAMETERS OVER IN THIS DIRECTION WERE THE ONES THAT HAD A MORE FREQUENT AMOUNT THAN WHAT YOU WOULD EXPECT AND DTI PROBABLY HAD ALSO VALUE, BUT THOSE ALSO HAD BEEN DEVELOPING SOPHISTICATED ANALYTICAL TOOLS DTI AND PUBLISHED IN THE IMAGE LAST YEAR, AND IT'S A MORE AUTOMATED METHOD. THIS IS USEFUL ON THIS AND AS WE MOVE FORWARD TO ADAPT IN KNEES TECHNIQUES THIS IS THE FILE OF WHAT WE WANT AND INDUCING INJURY AND SCANNING PICTURES OF THE HUMANS AND THIS IS THE CORTICAL CAPILLARY BED IN HUMANS, THESE ARE VERY FRYABLE AND BLOOD VEESORS THAT YOU SEE, ORTAGINAL, AND YOU SEE COMMONLY THESE ARE AFFECTED BY INJURY, WE'VE KNOWN THESE FOR A LONG TIME AND IT'S MEASURED USING HYPER CAPPIA, AND DILATE CEREBRAL BLOOD VESSELS AND INCREASE BLOOD FLOW MEASURES BOLD HYPER-ACTIVITY AS A WAY TO ASSESS VASCULAR REACTIVITY SO IN A NORMAL INDIVIDUAL, CAN YOU SEE THE CORTEX HAS EXQUISITE SER EASTBOUND BRAIL VASCULAR--ER EASTBOUNDERAL VASCULAR ACTIVITY AND WE BELIEVE THIS IS DECREASED AS WELL AS THE TBI. NO THAT'S IMPORTANT BECAUSE THERE ARE A LARGE NUMBER OF DRUGS THAT IN OTHER TISSUES ARE POSTULATED TO STIMULATE ANGIOGENESIS AND IN PRINCIPLE MANY OF THESE DRUGS ARE ON THE LIST OF THINGS THAT WORK ON RODENT MODELS OF TBI AND IN PRINCIPLE THEY MAY BE EXERTING NEUROPROTECTIVE EFFECT BY STIMULATING NEUROGENESIS. SO NOWY LET ME MOVE ON TO THE CLINICAL TRIALS THAT WE ARE ABOUT TO START HERE WITHIN NCRM, AND I THINK PROPOTENT STATEIN IS A FDA APPROVED COMPOUND AND APPROVED BY THE FDA FOR SEVERAL DECADES A LOT OF MODEL EVIDENCE, THAT IT IS AND NEUROPROTECTIVE STIMULATES AXONALLY REGENERATION AND ANGIOGENESIS AND THE STUDY WE WANT TO DO, THAT WE ARE WELL ON ITS WAY TO DEVELOPING IS TO DO A PHASE TWO TRIAL WITH ARITHROW POEITIN USING VOLUMEET RICKS WITH THE STUDY OF THAT. SO THE OTHER STUDY WE WANT THE TO TRY IS TO USE CENODEN O FILL, AND IT'S A POSTUREAISE FIVE INHIBITOR AND IT POTENTIATES NITRICRIX OCIDE AND THE INDEPENDENT DILATOR IN THE BRAIN LIKEWISE NEUROPROTECTIVE AS WELL AS PROMOTING ARMINGIO GENESIS, THIS WOULD BE A PILOT STUDY, MAULER SOMEBODY OF PATIENTS, AND THE PRIMARY OUTDOOR MEASURE THERE WOULD BE CENODEN O FILL, AND IT WOULD THAT MEASURING THE USE AND YOU WOULD HAVE TWO CONTROL GROUPS. AGAIN THE PRIMARY OBJECTIVE WILL BE THE MRI AND WE HAVE A NUMBER OF OF SECONDARY OBJECTIVES SUCH AS TOLERABILITY ET CETERA. THIS IS ANOTHER TRIAL THAT WE ARE AGAIN VERY FAR ALONG IN THE DEVELOPING AND START HERE WITH THE NEXT THREE OR FOUR MONTHS, DOESN'T USE MRI AS A BIOMARKER SO I WON'T TALK MUCH ABOUT THAT. SO THANK FIST YOUR ATTENTION AND I'LL PASS THE TOADIUM OVER TO DR. LATOUR NOW AND WHO WILL SHOW SMU OF THE WORK HE'S BEEN DOING HERE IN BETHESDA AND DC AREA OVER THE LAST COUPLE OF YEARS. >> SO, WHENEVER WE START THINKING ABOUT TBI, ONE OF THE FIRST THINGS THAT COMES UP IS THE POST CONCUSSIVE INCHROMES WITH THE SYMPTOMS--SYNDROMES WITH THE SYMPTOMS. I CAN'T HELP BUT THINK OF THIS PICTURE. WE'RE NOT GETTING ANYWHERE WITH THAT. THESE SYMPTOMS ARE NONSPECIFIC. PTSD AND TBI OVERLAP SIGNIFICANTLY AND WHEN WE ASK A PATIENT THAT PRESENTS ACUTELY, AND THEY DO HAVE A HEADACHE, YOU HAVE TROUBLE THINKING, CAN'T CONCENTRATE, BLAH, BLAH, BLAH AND THEY'RE LIKE, OF COURSE, I HAVE A KNOT THE SIZE OF AN EGG ON TOP OF A WATERMELON ON MY HEAD SO WE HAVE PROBLEM PROBLEMS SO I WILL TRY CO CONVINCE YOU OF THE NEURAL IMAGING. SO WE'VE KNOWN FOR OVER 150 YEARS THAT COMPLEX REPAIR RESIDES IN AN ORGAN THAT SYNTHESIZE THE SKULL, AND THEN W THAT ORGAN'S INJURED, BEHAVIOR CAN BE AFFECTED BUT FOR THE YOUNG PERSON THAT SUFFERS A TRAUMATIC BRAIN INJURY, THEY DON'T ALWAYS GET THIS, AND THERE'S 24 YEAR-OLD THAT'S PEDALING, HEADING DOWN THE STREET GETS T-BONED BY A 4000-POUND CAR IS IN THE HOSPITAL FOR A DAY OR SO, AND IS THERE FOR OTHER REASONS FOR TRAUMA AND GOES HOME AND RECOVERS AND SPENDS WEEKS AND MONTHS AND IN SIX MONTHS AND THEN HE STARTS HAVING PROBLEMS AND REALIZES THIS, AND CAN'T CONCENTRATE, HE'S A LITTLE BIT LESS INHIBITED, GIRL FRIENDS LONG GONE BECAUSE SHE FIGURED THAT OUT RIGHT AWAY AND AS OF A SUDDEN STARTING TO REG OUT AND NOBODY GET THIS IS, BECAUSE CLINICIANS THAT SEE THIS PATIENT ISN'T MAKING THE CONNECTION AND THE ORGAN IN THE SKULL HAS BEEN INJURED, DOES THIS CHANGE THE PICTURE? IF YOU CAN SEE THAT THE FRONTAL LOBE IN A PATIENT LIKE THIS HAS BEEN INJURED, YOU DON'T NEED MRI TO SEE THIS, CAN YOU SEE THIS ON CT, THEN MAYBE THAT, THAT GAP IS BRIDGED A BIT. THE GENERAL APPROACH TO MOST MILD TBI STUDIES, HAS BEEN LIKE OTHERS, HYPOTHESIS DRIVEN, STARTS OFF WITH A GUESS AND YOU DEFINE TWO GROUPS AND USUALLY IT READS SOMETHING LIKE DIGITEXT MILD TBI VORCES CONTROLS. THE PROBLEM WITH THIS IS THAT THE DIAGNOSIS OF MILD TBI, WE DON'T HAVE A GOOD DIAGNOSIS FOR THAT, SOMETHING THAT IS TRULY OBJECTIVE AND THIS IS A STUDY OR A PROJECT BY MARY JO RUCKER AT SUBURBAN HOSPITAL AND THESE ARE PATIENTS WE'VE SEEN THAT HAVE SYMPTOMS OF CONCUSSION BASED ON POSITIVE LOSS OF CNESS AND DEFINED POST-TRAUMATIC AMNESIA AND LESS THAN 15, AND WHETHER THERE WAS AN AFFIRMATIVE DIAGNOSIS OF CONCUSSION OR MILD TBI IN THE MEDICAL RECORDS THEY DON'T EXIST, AND THIS IS NOT A CRITICISM OF SUBURBAN HOSPITAL, IT'S JUST NOT THAT CRITICAL IN THE EMERGENCY ROOM TO LABEL SOMEBODY AS HAVING A CONCUSSION AND HAVING THAT OFTEN, IN FACT, 50% OF THE PATIENTS THAT WE SEE THAT MET THE RITERRIA FOR CONCUSSION WEREN'T DIAGNOSED WITH CONCUSSION, BUT REASONS WHY. WE WANT TO DEVELOP A TOOL TO DIAGNOSE CONCUSSION BUT WE DON'T HAVE A GOLD STANDARD, WE DON'T HAVE A CONCUSSION, IT'S A DIFFERENT PATIENTS IN THE CLINIC THAT YOU ARE THAN WHAT WE HAD FOR STROKE BUT NOT TERRIBLY DIFFERENT SOME WAYS SO I WANT TO REDEFINE THIS APPROACH A LITTLE BIT, LOOK AT POPULATION BASED APPROACH, USUALLY THIS IS SUCH A NEGATIVE WORD, EXPLORATION BECAUSE IT'S A POINT OF A FISHING TRIP, LOOKING FOR, WE'RE GOING OUT AND LOOKING FOR TRYING TO SEE WHAT WE NEED TO SEE AND WE DON'T KNOW WHAT WE'RE LOOKING FOR, BUT, THE GOAL WOULD BE TO SOMEHOW COME UP WITH IMAGING OR SOMETHING WE CAN PLACE A PATIENT IN A BOX SAYING, YES WE SEE OBJECTIVE EVIDENCE IN THIS INJURY IN THE BRAIN, BUT STARTING HERE IS A PROBLEM BECAUSE MOST CT SCAN SYSTEM CT IS WHAT'S DONE CLINICALLY, ACUTELY TO RULE OUT INJURIES THAT COULD BE LIFE CHANGING, SUBDURAL HEMATELOMERA, REQUIRES INTERVENTION AND IT'S EFFECTIVE AT DOING THAT, YOU KNOW? WE CAN'T DISPLACE THIS WITH MRI, STROKE WE MAY TRY TO DISPLACE CT WITH MRI WITH A LOT OF CONTROVERSY IN THE ACUTE SETTING, CT IS GOING TO BE HARD TO SAY BUT IT LEADS YOU TO THE IMPRESSION THAT PATIENTS THAT HAVE A NEGATIVE CT DON'T HAVE INJURY, RIGHT? OR THE CTs INSENSITIVE TO THAT AND THEN IT'S SORT OF SO WHAT, THIS IS BACK IN 1992, WHERE THE STROKE, UNTIL THE FUSION WEIGHTER CAME ALONG AND IN 92 AND 95, WHEN THE THERAPY CAME OUT, WE DIDN'T NEED A DIAGNOSIS OF THE CLINICAL DIAGNOSIS, CT WOULD RULE OUT HEMORRHAGE AND IT WAS GOOD AT DOING THAT, WE KNOW NOW AFTER 12 YEARS OF THE HOSPITAL AT NIH, THERE'S A HIGH OVERHEAD FOR THE CLINICAL DIAGNOSIS, RIGHT? ROUGHLY A THIRD OF THE PATIENTS THE CLINICAL STROKE TEAM SEES, DO NOT HAVE STROKES, THEY HAVE STROKES OR SOMETHING ELSE, DIFFUSION IMAGING HAS A VERY HIGH SENSITIVITY AND SPECIFICITY, AND APPROACHES NEARLY A HUNDRED%, 95 TO 98%, AND IF IT'S NEGATIVE, THERE'S A HIGH PROBABILITY AND THERE'S A REASONABLE APPROACH TO WHAT WE'RE DOING, IT BASED ON IMAGING OF MORE SEVERELY INJURED TRAUMATICALLY INJURED PATIENTS WE IMAGED THESE GUYS WITH CT OR GROUPS IMAGING THEM, AND WE UNDERSTAND THE PATHOLOGY IN THESE SEVERE PATIENTS IS SIMILAR TO THAT, EDEMA HEMORRHAGE, BLOOD-BRAIN BARRIER AND THIS LEADS TO TISSUE AND ATROPHY, BUT COMPARED TO ANY PLACE IN THE WORLD IT'S AS GOOD AS IT GETS FOR DIAGNOSES AND TREATING ACUTE STROLL IN THE EMERGENCY ROOM, THE STROKE TEAM HAS SEEN ROUGHLY 10,000 PATIENTS NOW AND IN SEEING THESE STROKE PATIENTS, WE'VE HAD ANECDOTA CASES THAT HAVE HAD FALSE STROKES, SO THIS COMES TO THE GENESIS OF WHAT WE ARE NOW CALLING THE TRAUMATIC HEAD INJURY CLASSIFICATION STUDY, AND IT'S SUPPORTED BY THE INFRASTRUCTURE AND NEUROSCIENCE REGENRATIVE MEDICINE AND THIS IS SORT OF A CONTEXT IS TO PROVIDE THE OBJECTIVE RATIONAL FOR IDENTIFYING PATIENTS WITH POSITIVE TRAUMATIC BRAIN INJURY AND TO TENTIALLY IDENTIFYING NOVEL MARKERS AND INDUCTOR SORT OF IDENTIFIED RIGHT AND IF WE HAVE A THERAPY THAT MEANT TO ADDRESS FOR INSTANCE INFLAMMATION AFTER A HEAD INJURY, WE WANT--TBI, PARTICULARLY IF MILD CASE, VERY, VERY, HETEROGENEOUS WANT TO IDENTIFY PATIENTS OBJECTIVELY THAT HAVE INFORMATION AND THAT'S OUR BEST SHOT AT TESTING WHETHER OR NOT THERAPY WORKS AND IT'S NOT OUR UNIQUE IDEA THIS, IS MODELED AFTER WHAT WE TRIED TO DO WITH THE STROKE. SO NOW IT'S TIME FOR THE AUDIENCE PARTICIPATION STROKE, TEAM AND TBI TEAM AND LEFT OUT AND SO I'M GOING TO SHOW YOU PATIENTS AND STROKE AND TBI AND THEY'RE BOTH MILD AND YOU HAVE TO TELL ME WHICH IS THE STROKE AND WHICH IS THE TBI. SO DIFFUSION CAN DUST THIS OUT IN THE RADIOLOGYSTS IN THE ROOM, SO THE FUSION IMAGES WHEN THE--METABOLIC SUBSTRATE FOR FUNCTION OF TISSUE IN THE BRAIN DECREASES, CELLS DEPOLARIZE AND WHEN THEY DEPOLARIZE THEY SWELL AND REDUCE THE AMOUNT OF PREWATER AND MOLECULES CAN MOVE, AND THE DIFFUSION CO EFFICIENT IN CDC, AND DTI, AND RESULTS IN A HYPER INTENSITY ON DWI, STROKE, STROKE? TBI? ANYONE THIS, IS AN EASY ONE. ANTERIOR SEER CEREBRAL ARTERY AND IN THIS AREA, THE CORPUS CO LOSS UMKC THAT'S INJURED, SECOND PATIENT IS DIFFICULT, SO ON THIS TTWO IMAGING, DLEOSEIS AND5pw WATER, THE BLOOD-BRAIN BARRIER IS WATER, SKELS AND VASCULATURE INTO THE TISSUE, RESULT IN A HYPER INTENSITY AND ELONGATION OF THE TTWO VARIABLE, T-TWO REAXATION CONSTABILITY AND IT APPEARS PROPRIETARY BRIGHTER ON TTWO OR TTWO FLAIR IMAGES OR STROKE OR TBI, ANY THOUGHTS IN. --THOUGHTS? ONE ON THE LEFT IS. >> VASCULATURE ALSO GETS AFFECTED AND LEAVES A TTWO TREATMENT CONTRAST AND POST CONTRACT IMAGES AND LEAKS INTO THE FREE ACCESS SPACE AND ONE IS A STROKE AND ONE IS A TBI, AND THEN HEMATELOMERA WE HAVE IMAGING, I'LL BACK UP AND SAY MORE ABOUT THIS WITH THE TBI, SEQUENCES THAT ARE CENSUS TO BLOOD AND AGAIN ONE IS A PRIMARY INJURY, CAUSED BY TRAUMA AND THE OTHER ONE IS THE RESULT OF A HEMORRHAGIC LESION RESULT NOTHING HYPOINTENSITY AND THIS IS THE PATIENT WITH THE STROKE AND HOPEFULLY THIS IS NOT A RETRIEVAL VERSION AND CAN YOU SEE THE FRONTAL LOBE INJURY HERE, AND THERE'S SOMETHING MORE SUBTLE IN ANOTHER SEQUENCE THAT SENSES TO BLOOD, THAT'S MORE SENSITIVE BECAUSE OF THE WAY THAT THE SEQUENCE IS EXECUTED, SUSEPTIBILITY WAY THEY RECEIVE THE BLACK HOLES THAT IN STROKE WE THINK ARE RELATED TO ANG I DON'T MEANATHY AND IN TBI ARE RELATED TO TRAUMA, SO YOU'RE GETTING THE PICTURE, AND THIS IS IN RELATION TO 60 STROKE TIA AND MIMICS AND WHAT WE FOUND WAS IN THE--I WON'T SAY MUCH ABOUT THE COMPARISON BUT IN THE PATIENTS THAT HAVE MILD TBI, WE FOUND IMAGES DEFINED ROUGHLY ON MRI AND ROUGHLY 50% OF THOSE AND IN THOSE THAT HAD A CT SCAN AND CT WAS NEGATIVE ABOUT 80% OF THOSE. HALF OF THEM HAD THESE SCAN SYSTEM SO FIRST LET'S LOOK AT CATEGORIZATION WITH THE CT AND THE CT POSITIVE PATIENTS WHICH IS REALLY WHAT CT IS THEREFORE SEVERE INJURY PROBLEM IS THESE GUYS ARE ALSO VERY MILD. A VERYICISM POLITIC WAY OF THINKING ABOUT THAT, THE CT SCAN IS CATEGORIZED INTO SOMETHING THAT SEEMS FAIRLY PROMISING. --WHICH THEY MOT REPRESENT THE BRAIN INJURY, THE VASCULATURE OF BLOOD THERE BUT NOT NECESSARILY INJURY TO THE TISSUE AND THEN THERE'S OTHER THINGS WE SEE ON CT THAT ARE SENSITIVE TO THE TISSUE AND THEN THIS IS A PATIENT THAT'S FAIRLY EARLY AFTER AN INJURY, THEY BOTH CT STANS, CT SCANS THE BONE ABSORBS EXTRA AT A GREATER RATE THAN TISSUE, THAN CSF, AND BLOOD APPEARS IN BETWEEN THE TISSUE AND THE BONE AND THE HEMORRHAGE HERE, YOU SEE A SMALL HEMATELOMERA HERE THAT'S PROBABLY, RADIOLOGYSTS THAT CAN PICK THAT UP AND I WOULDN'T PICK THAT UP, THIS OVER24 HOURS AND THIS IS A HEMATELOMERA, BUT A LOT OF PATIENTS NEVER GET TO THIS POINT, HAVE YOU A SMALL AMOUNT OF THE HEMORRHAGE, SO IF YOU IGNORE THE TISSUE INJURY IN THIS PARTICULAR PATIENT, JUST THINK ABOUT THE EXTRA ACTIVE BLOOD, AND THIS IS AN IDEA THAT CAME FROM RAMOAN ACTUALLY BECAUSE MR WOULD BE INENTIOUS FICIENT TO DO THESE PATIENTS AND SCREENING THEM FOR CLINICAL TRIAL, IF WE JUST TAKE THE PATIENT THAT HAVE CT SCANS AND ON THE CT SCANS THERE'S NOTHING OR EVIDENCE OF ONLY EXTRA AXIAL HEMORRHAGE, 84% OF THOSE PATIENTS THAT HAVE EVIDENCE ON CT SCAN OF OF EXTRA AX VAL BLOOD HAVE EVIDENT OF PATHWAY GIVES RINK MALINJURY ON MRI, SO BASICALLY SAYING CT IS A GOOD PREDICTER, CT IS A GOOD PREDICTER OF INJURY TO THE BRAIN ON MRI. THERE'S PINGS ALSO A LARGE POPULATION OF PATIENTS THAT HAVE A NEGATIVE CT SCAN THAT HAVE IMAGING FINDINGS AND THESE ARE ALSO INTERESTING, BUT STILL LET'S TICK WITH THE ONE PATIENT. WHAT I'LL SHOW YOU NOW THIS, IS A FLARE, FLARE SUGGESTED GLEEL, INJURY TO THE TISSUE, LOTS OF TIME STROKE PATIENTS HAVE MATTER TO THE DISEASE, THEY HAVE AN INFARCTION AND YOU SEE GLEEL CELLSOSEIS AND HERE CAN YOU SEE A LITTLE BIT OF INJURY AND THIS WAS TAKEN 90 DAYS AFTER, NOW THINK ABOUT THIS PATIENT, THE BIKER THAT'S HEADING DOWN THE TREAT THAT CAN'T QUITE, OR THE SERVICE MEMBER THAT CAN'T QUITE FIGURE OUT WHY HE'S HAVING THESE SYMPTOMS, AND YOU COMPARE THIS SCAN TO THE SCAN THAT IS OBTAINED WITHIN THE FIRST DAY ON MR. HOPEFULLY THIS WORKS. TRY THIS ONE MORE TIME. NOW, DEM- FROM THE INJURY THERE, BUT WE AT LEAST NOW KNOW THAT THIS WHOLE AREA WAS INVOLVED IN THE ACUTE INJURY AND THIS MAY BE SOMETHING THAT WE CAN INTERVENE IF THIS RESULTS IN PERMANENT IMPAIRMENT AND AGAIN THIS IS THE IMAGES THAT THEY'RE TRYING TO FIGURE OUT WAYS TO IDENTIFY THIS MORE OBJECTIVELY WITH THE COMPUTATIONAL METHODS BUT WE SEE THE INJURY, SO WE SEE LOSS OF GRAY MATTER THERE AND YOU COMPARE IT TO DAY TWO SCAN AND WE FIRST WE GOT SO WE GOT INJURY, SO THE POINT IS THAT THE INJURY THIS THESE PATIENTS WE KNOW HAVE INJURY, DISAPPEARS AS TIME FROM THE INJURY PROGRESSES. SO NOW WE'LL LOOK AT LITTLE BIT AT THE MILDER INJURY AND THE CTNEGGATIVE STATIONS AND SO THERE'S A PRESUMPTION THAT THOSE PATIENTS THAT A CT NEGATIVE, REALLY ONLY TWO EXPLANATIONS EITHER, THEY DON'T HAVE INJURY, OR CTs SENSITIVE TO INJURY AND IT'S FALSE-NEGATIVE FOR IT AND INJURY AND I LOVE PRESENT THANKSGIVING PATIENT IF YOU SEE IT BEFORE AND IT'S THE PERFECT REASON WE'RE DOING THIS. AND 47 YEAR-OLD MALE THAT YOU KNOW A Ph.D., WORKS AT THE ROOF OF AND IT'S A DIFFERENT QUESTION, BUT HIS WIFE FOUND HIM ON THE BED AND HE WAS OUT FOR MAYBE FIVE MINUTES WITH ABOUT FIVE-15 MINUTES OF POST-TRAUMATIC AMNESIA AND CONFUSED COMBATIVE AND YOU COULD TALK TO HIM. HE WASOT BORDER OF PROVIDING SELF-CONSENT AND HIS WIFE CONSENTED HIM. THE CT SCAN WAS NEGATIVE, THIS IS THE MRI, ON PATIENT, AND FIVE DIFFERENT SEQUENCES HERE, YOU CAN SEE THESE TRAUMATIC MICROBLEEDS THAT ARE ON THE HIGHER EASE LUGES IMAGES AND CYTOTOXIC EDEM IN THEOX SIPTAL LOBE, EDEMA ASSOCIATE WIDE THE MICROBLEEDS AND ENHANCEMENT IS WHAT I'LL SPEAK MORE ABOUT ON THE POST CONTRAST IMAGES. I WILL FOCUS ON THESE TWO, THAT ARE NOVEL. I'LL EXPLAIN IN MORE DETAIL. THE SO THE SUSEPTIBILITY WEIGHTED IMAGES HAS BEEN AROUND A WHILE AND PATIENTS WITH A LOT OF THESE SMALL MICROBLEEDS AND THE MICROBLEEDS WE THINK ARE RELATED TO ION DEPOSITION, AMLLOYD ASSOCIATED WITH AMLLOYD DEPOSIT, AND RISK OF HEMORRHAGE IF WE GIVE THEM TPA BUT THEY'RE PREEXISTING IN RELATION TO SOME OLDER POPULATION AND THESE TTWO STAR TECHNIQUES WE USE IN THE HYPER ACUTE PATIENT SETTING BECAUSE WE GET THEM IN AND HOW THE, IT TAKES ABOUT TWO MINUTES. PROFUSION WEIGHTED SCAN, WE GET THE WHOLE BRAIN AND REPEAT THIS EVERY 1.5 SECONDS AND YOU CAN SEE THESE MICROGLEES AND CAN YOU SEE THE ADVANCED TBI, THAT YOU HEAR ABOUT IS THE HIGHER RESOLUTION SUSEPTIBILITY WEIGHTED IMAGING THAT VERY NICELY VISUALIZE THE VESSEL AND THE EXTENSION MICROWAVE, THE PROBLEM WITH THESE SCANS IS THAT WHILE THE SENSITIVITY GOES UP DRAMATICALLY,S5? THERE'S A LOT OF BLACK STUFF ON SKIN, IT'S DIFFICULT TO PICK UP WHAT'S REAL AND WHAT'S PATHOLOGY AND WHAT'S NATURAL. VESSELS THERE, WHAT WE'VE BEEN SEEING WITH THIS LOWER RESOLUTION SCAN THAT'S MUCH GRAYER, DON'T SEE THE VESSELS, VERY SIMILAR TO WHAT WE SEE IN STROKE AND SOME CASES, THEY'RE ROUNDER, THE SAME DIMENSION, SAME SIZE IN ALL DIMENSIONS, ANOTHER KIND OF MICROGLEE OR OTHER PEOPLE SEE, HAVE NOT MADE THE CONNECTION THAT GO THROUGH THE WHITE MATTER AND IF YOU LOOK IN THE--AGAIN, AXIAL SLICE, THIS IS SAGETAL, THE FRONT OF THE BRAIN, THE BACK, THE BOTTOM THE TOP, LEFT AND RIGHT, YOU CAN SEE THE DROP OFF THAT FOLLOWS A LINEAR PAD AND YOU CONTRACT IT ALL THE WAY UP TO THE MENINGIS AND WE SEE THEM ON THIS SIMPLE 1.5 TESLA STAR SEQUENCE OR HOW LONG IS THE--[INDISCERNIBLE] ON THE--DO YOU SOMEONE--DO YOU KNOW? SO EIGHT TO 10 MINUTES, SO DEPENDING ON THE BETTER SCAN, YOU SEE THE STROKES YOU'RE NOT MISSING, THERE'S MORE MICRO STRUCTURES HERE BUT WE'RE NOT MISSING THE BIGGER STRUCTURES HERE SO IF WE COMPARE THE FINDINGS, THESE HYPER INTENSITY EARN THE ORDER OF 10 TO 15%. COMPARE THEM TO THE MICROBLEEDS AND THE PATIENTS WHO HAVE MICROBLEEDS AND THOSE THAT HAVE LOTS OF HIGH POINTS TEND TO BE BRACHING LIKE THIS, AND HEMATELOMERA HEMORRHAGE AND SUBDURAL HEMATELOMERA, HETEROGENEOUS GROUP, ALL IN THE ORD EVERY OF 10 TO 30% PREVALENT IN ALL PATIENTS IN THE HOSPITAL AND THAT IS DWARFED BY OTHER FINDING THAT WE'RE NOT SURE WHAT TO MAKE. THIS IS THE PATIENT THAT WE SAW ABOUT TWO WEEKS AGO, AND CAN YOU SEE THE EGG ON THE HEAD, SHE'S OLDER, ON COUPA DIN AND THIS IS A LARGE CONTUSIONOT OUTSIDE DOES YOU CAN SEE BILATERAL SUBTELOMERA, I'M POINT THANKSGIVING OUT BECAUSE THERE'S A MISCONCEPTION ABOUT WHERE THE SUBDURAL BLOOD GOES THAT THERE'S A KAFIT SOMEWHERE BETWEEN THE ARACHNOID MEMBRANE. AND THESE CELLS CONNECT THE DURA TO THE MEMBRANE. THE GAB LYNNIUM WE GIVE THE PATIENT ISSUES THIS IS A FLARE AND ENHANCES THE DURA AND THAT THICKER LAYER THIS IS A GREAT THREE DIMENSIONS YOU CAN SEE THIS IS I COMPLEX PHENOMENA THAT VOID WITH THE GABBA LYNNIUM WHERE IT'S NOT AND IN PATIENT WHERE IS WE SEE THIS ENHANCEMENT CALLING TRAUMATIC INJURY, IN 85% OF THEM WE'RE SEEING IN [INDISCERNIBLE] VARIES ALL OVER, WE DON'T SEE IT IN THE OCCIPITAL LOBE, PATIENTS PLAYING ON THE BACK OF THE HEAD AND SOME CASES, IT'S PROBABLY FLUID FILLED SPACE IN THE BRAIN, WEIGHT OF THE BRAIN IS OUT AND TO THE SIDE. IT HAS AND IT HAS VARIOUS DEGREES OF PILOT PROJECT CUITY, AND IT'S A LITTLE BIT MORE CONSPICUOUS AND OTHER TIMES IT'S SPACE OCCUPIED, OUT OF 141 PATIENTS WE'VE HAD CLOSE CONTRAST ON, IT SPLIT SPLITA THIRD IN THAT GRADE AND BY DAY FOUR IT'S GONE AND ROUGHLY 40% OF THE PATIENTS AND BY 30 AND 90 DAYS GONE AND ROUGHLY 3-QUARTERS OF THE PATIENTS COME BACK, SO WE DON'T KNOW WHAT IT MEANS, IT RESOLVES OVERALL STRATEGY A PERIOD OF--OVER A PERIOD OF TIME, THAT WE THINK SYMPTOMS RESOLVE IN THE POST CONCUSSIVE SYNDROME BEGINS TO RESOLVE AND THE MENINGIS ARE ACTIVATED IF YOU RUPTURE THE DURA, THERE'S A HEADACHE THAT RESULTS FROM THIS. AND IN A FEW CASES, PARTICULARLY THE ELDERLY PATIENTS, THIS IS AGAIN, PRECONTRAST, CONTRAST ACUTELY AND IT PROGRESSED TO A CHRONIC SUBDURAL HEMATELOMERA SO SHOULDN'T MAKE TOO MUCH OF THAT. SO THIS PATIENTS A DIFFERENT PICTURE OF WHAT WE HEAR ABOUT IN THE LITERATURE, AND INDIRECTLY TO THE BRAIN AND THIS' A PROPOSITION THAT MAYBE INJURY IS NOT THE BRAIN ITSELF, BUT INJURY PRIMARILY TO THE VASCULATURE AND INFORMATION AND MICROBLEEDS AND LINEAR STRUCTURE, MAYBE ALL PART OF THE TYPE OF INJURY, SO IN THE RESPONSIVE TIME SO HAVE YOU A CHANCE TO ASK QUESTIONS, I'M GOING TO SKIP RIGHT AHEAD, MY CLINICAL FRIENDS, AND PHYSICIANS DO HAVE SOME THAT ARE FRIENDS REMINDLY CONSTABILITILY AT SOME POINT WE HAVE TO GET TO THE SO WHAT QUESTION, WHAT DOES THIS MEAN FOR THE PATIENTS AND THE CLINICIAN? WE'RE NOT QUITE THERE YET. TO PUT IT IN PERSPECTIVE IN THE 12 YEARS, OF COURSE THAT WE'VE DONE ON STROKE, WE'RE IN THE ORDER OF 10,000 PATIENTS AND THE NUMBER OF PATIENTS AT A SCENE ACROSS THE COUNTRY FOR ACUTE STROKE AND IT'S WELL ORGANIZED RIGHT NOW IS ASTRONOMICAL COMPARED TO WHAT WE'RE DOING RIGHT NOW, MILD BRAIN INJURY AND WE HAVE TO HAVE REASONABLE PATIENTS THAT ONE STEP AT A TIME WE'LL GET THERE. AND I THINK IT'S RECOGNIZABLE INJURY TO THE BRAIN RESULTS IN THE CHANGE IN BEHAVIOR. THERE'S A LOT OF PEOPLE I NEED TO THANK INCLUDING ACUTE TBI TEAM, [INDISCERNIBLE] STROKE TEAM WHOSE FOOT STEPS WHERE TRYING TO FOLLOW AND THE HOSPITALS AND THE PATIENTS. THANK YOU MPLET [ APPLAUSE ] --THANK YOU.