GOOD AFTERNOON AND WELCOME TO THE LAST GRAND ROUNDS PRESENTATION OF 2012 TODAY WE ARE GOING TO HAVE TWO SPEAKERS FOCUSNG ON NEUROSCIENCE. OUR FIRST SPEAKER IS DR. MARK MATTSON WHO IS CHIEF OF THE NATIONAL INSTITUTE OF AGING LABORATORY OF NEUROSCIENCE AND A PROFESSOR IN THE DEPARTMENT OF NEUROSCIENCE AT JOHN HOPKINS. DR.MATTSON EXPERTISE IS IN CELLULAR AND MOLECULAR MECHANISM UNDERLYING NEUROMANY DEGENERATIVE DISEASES. HE HAS MADE MAJOR CONTRIBUTIONS TO UNDERSTANDING THE PATHOGENSIS OF ALZHEIMER DISEASE, PARKINSON DISEASE AMILATROFIC LATERAL SCLEROSOS AND STROKE AS WELL AS THEIR PREVENTION AND TREATMENT. DR. MATTSON EARNED HIS PHD IN BIOLOGY AT THE UNIVERITY OF IOWA AND COMPLETED HIS POST DOCTORATE FELLOWSHIP IN DEVELOPMENTAL NEUROSCIENCE AT COLORADO STATE UNIVERSITY HE THEN JOINED THE SANDERS-BROWN CENTER ON AGING IN THE DEPARTMENT OF ANATOMY AND NEUROBIOLOGY AT THE UNIVERSITY OF KENTUCKY COLLEGE OF MEDICINE IN 1988. HE BECAME A FULL PROFESSOR THERE IN 1997. IN 2000 HE MOVED TO THE NIH AND JOHN HOPKINS SIMULTANEOUSLY TO UNDERTAKE HIS CURRENT POSITION AND PRIOR TO HIS APPOINTMENT HE RECEIVED VARIOUS NIH EXTRAMURAL AWARDS AND SERVED ON THE BOARD AS AN AD HOC REVIEWER. DR. MATTSON HAS BEEN ACTIVE INTERNATIONALLY ON ADVISORY BOARDS AND COUNCILS AS EDITOR IN CHIEF AND MANAGING ASSOCIATE EDITOR OF SEVERAL JOURNALS AND AS A MEMBER OF SEVERAL PROFESSIONAL SOCIETIES. HE WAS ELECTED AS A FELLOW OF THE AAAS AND HAS RECEIVED MANY AWARDS, MEDICAL RESEARCH AWARD, THE ALZHEIMER'S ASSOCIATION ZONETH AWARD, AND THE [INDISCERNIBLE] CHAIR PRIZE IN -- FROM SPAIN, AND MOST RECENTLY, THE [INDISCERNIBLE] AWARD IN ISRAEL. AND THE TITLE OF HIS TALK TODAY IS TWEAKING ENERGY METABOLISM TRY PREVENT AND TREAT NEUROLOGIC DISORDERS. WELCOME. >> THANKS FOR THE KIND INTRODUCTION. WHAT I'M GOING TO TELL YOU TODAY IS THAT IT'S IMPORTANT TO CHALLENGE YOUR NEURONS ENERGICALLY THROUGHOUT YOUR ADULT LIFE IN ORDER TO INCREASE THE CHANCES THAT YOU DON'T DEVELOP AN AGE RELATED NEURO DEGENERATIVE DISORDER. I HAVE NO COMPETING INTEREST. THESE ARE THE OBJECTIVES. TO EXPLAIN HOW BRAIN CELLS RESPOND TO CHANGES IN ENERGY INTAKE, DIETARY ENERGY INTAKE. EXERCISE. VIB IS FALLING -- DESCRIBE THE SIGNALING PATHWAYS EFFECTED BY AGING AND MAY BE COMPROMISED IN NEURO DEGENERATIVE DISORDERS. AND AN AREA WE HAVE BEEN WORKING ON QUITE A BIT LATELY, THAT'S THE RELATIONSHIPS BETWEEN NEURO TROPHIC FACTORS WHICH ARE FAMILY OF PROTEINS THAT AS THE NAME IMPLIES, ARE INVOLVED IN THE GROWTH AND PLASTICITY AND SURVIVAL OF NEURONS. THE RELATIONSHIP BETWEEN SIGNALING PATHWAYS UTILIZED BY THOSE FACTORS, AND ENERGY METABOLISM. NOT ONLY NEURONAL METABOLISM BUT WHOLE BODY ENERGY METABOLISM. WHAT'S THE TRANSLATIONAL IMPLICATIONS OF THIS WORK. IF I DON'T FINISH IN TIME, I WROTE AN ARTICLE THAT COVERS MOST WHAT I'M GOING TO TALK ABOUT TODAY FOR THE JOURNAL CELL METABOLISM. THIS IS AN AGE DISTRIBUTION IN THE AMERICAN POPULATION, 2010, 2030, 2050. MALES, FEMALES. EACH BAR, FOR EXAMPLE, THIS 20-YEAR OLD BAR RIGHT NOW, THERE IS ABOUT 2 MILLION MALES THAT ARE EXACTLY 20 YEARS OLD. MAYBE A COUPLE HUNDRED THOUSAND INCREASE IN THE NUMBER OF 20-YEAR OLDS OVER THE NEXT 30 YEARS. AND THEN ABOUT ANOTHER -- BY 2050 THERE WILL BE ABOUT A MILLION MORE. IF WE LOOK IN THIS AREA, AGE RANGE, RIGHT NOW THERE IS ABOUT 1 MILLION MALES WHO ARE 70-YEAR OLDS. THAT WILL DOUBLE IN THE NEXT 20 YEARS. THE REASON IS PARTLY BECAUSE OF THE BABY BOOMERS. BUT ALSO BECAUSE ADVANCES IN CANCER RESEARCH, CARDIOVASCULAR DISEASE AND DIABETES TO THE EXTENT THAT MANY INDIVIDUALS THAT WOULD HAVE DIED WITHIN THIS AGE RANGE ARE LIVING INTO THE DANGEROUS ZONE AGE RANGE FOR ALZHEIMER'S AND PARKINSON'S DISEASE. I'M GOING TO FOCUS IN MUCH OF MY TALK IN A REGION OF THE BRAIN CALLED THE HIPPO CRAMPIS, CRITICAL FOR LEARNING AND MEMORY. NEURONS DEGENRATE IN ALZHEIMER'S DISEASE. WHAT I'M GOING TO TELL YOU, IT'S IMPORTANT TO CHALLENGE NEURONS IN THE BRAIN REGION AND OTHER REGIONS DURING ADULT LIFE. WHAT I MEAN BY CHALLENGES ARE MILD INTERMITTENT STRESSORS. EXERCISE IS A STRESS WHEN YOU'RE EXERCISING, NOT ONLY ON YOUR MUSCLES, BUT ACTIVITY IN YOUR NERVE CELLS AND A LOT OF BRAIN INCREASES DURING EXERCISE, SO AN ENERGETIC STRESS, INCREASE PRERADICAL PRODUCTION. WHAT WE'RE FINDING, SIMILAR TO YOUR MUSCLE CELLS DURING EXERCISE, PATHWAYS ARE ACTIVATED IN NERVE CELLS IN RESPONSE TO EXERCISE, ALSO IN RESPONSE TO NOT EATING FOR AN EXTENDED TIME PERIOD, FASTING. ALSO IN RESPONSE TO WHAT WE'RE DOING NOW, HOPEFULLY USING OUR NERVE CELLS. ING THERE IS HE INCREASED NEW YORK DEMAND, INCREASED FREE -- RADICAL PRODUCTION. GENES ENCODE PROTEINS THAT HELP THE CELLS COPE WITH THE STRESS. ONE THING I'M GOING TO TALK ABOUT, UPREGULATED IN THE HIPPOCAMPUS IN RESPONSE TO EXERCISE, FASTING. AND KEEPING YOUR NERVE CELLS ACTIVE. BRAIN DERIVED NEUROTROPIC FACTOR, BDNF. IT'S PRODUCED IN RESPONSE TO EXCITERY ACTIVATION OF SYNAPSES HERE. AND MANY LABS HAVE SHOWN THAT BDNF DOES MANY GOOD THINGS FOR NEURONS. IT'S CRITICAL FOR LEARNING, MEMORY, WHAT WE CALL SIN ANTIC PLASTICITY, GROWTH AND STRENGTHENING. CRITICAL FOR THE SURVIVAL OF NEURONS AND CAN PROTECT NEURONS AGAINST ADVERSE CONDITIONS OCCURRING DURING AGING, INCLUDING OXIDATIVE STRESS. PROBLEMS WITH MITOCHONDRIAL ENERGY PRODUCTION, AND WE'RE ALSO FINDING -- I'LL SHOW YOU A BIT OF DATA THAT BDNF CAN INCREASE THE NUMBER OF MITOCONDRIA NERVE CELLS SIMILAR TO WHAT HAPPENS IN YOUR MUSCLE CELLS WHEN YOU EXERCISE THEM. FINALLY, THERE ARE NEURAL CELLS NICAL DIFFICULTIES] PUT RUNNING WHEELS IN THE CAGES OF MICE OR RATS AND LET THEM RUN FOR TEN DAYS, A COUPLE WEEKS, AND THEN QUANTIFY NEURO GENESIS, THE PRODUCTION OF NEW NEURONS FROM STEM CELLS, IT'S GREATER IN THE RUNNERS THAN IN THE SEDANTRY ANIMALS. SO THIS SHOWS -- THE BLACK HERE, EVERY BLACK DOT HERE IS A NEWLY GENERATED CELL THAT HAS BEEN GENERATED FROM A STEM CELL. MANY OF THESE CELLS WERE DIFFERENTIATE IN THE NEURONS. THESE CELLS ARE LABELED WITH GFP IN A RETRO VIRUS, LABEL NEURONS THAT HAVE ARISEN FROM STEM CELLS. THIS WAS SEVERAL WEEKS OR EVEN A MONTH AFTER LABELING. AND IN A RECENT PUBLICATION IN NATURE COMMUNICATIONS, HENRY THE'S LAB, AND OTHERS WAS ABLE TO LABEL NEWLY GENERATED NEURONS WITH DFP USING A RETROVIRUS AND USING A RABIES VIRUS WITH A RED FLOORO CHROME. SHE WAS ABLE TO LABEL ANY NEURONS THAT FORM SYNAPSES WITH THE NEWLY GENERATED NEURONS, RABIES IS TRANSFERRED RETRO GRADELY, SO SHE INFECTS THE NEWLY GENERATED NEURONS, ANY NEURON THAT FORMS SYNAPSES. WHAT SHE DID WAS PUT A PATCH CLAMP ELECTROYED IN NEWLY GENERATED NEURON, ONE IN ONE OF THESE NEURONS THAT FORMED SYNAPSES, AND OVER A PERIOD OF DAYS, 25 DAYS, 30 TO TWO MONTHS, SHE LOOKED AT THE ENERVATION OF THESE NEWLY GENERATED NEURONS AND DEVELOPED A TIME COURSE OF WHICH NEURONS FIRST FORMED SYNAPSES WITH THE NEWLY GENERATED NEURONS, AND WHAT'S THE SEQUENCE. IF YOU'RE INTERESTED, IT'S INTERESTING. BUT BOTTOM LINE, SHE FOUND THAT ENTRANCE NEURONS FORMED SYNAPSES WITH THE NEWLY GENERATED NEURONS. LATER, NEURONS FROM THE CORTEX, MEDIAL [INDISCERNIBLE] CORTEX HERE, FORMED SYNAPSES. OKAY. I MENTIONED THAT IF YOU PUT RUNNING WHEELS IN THE CANES OF MICE YOU GET INCREASED NEURO GENESIS. ONE FUNCTION OF THE DENTIA GIRUS, OUR ABILITY TO REMEMBER WHERE DIFFERENT OBJECTS ARE LOCATED IN OUR ENVIRONMENT. OBVIOUSLY, THAT'S VERY IMPORTANT. WE'D BE IN TROUBLE IF WE COULDN'T DO THAT. IF YOU LESION IT IN ANIMALS, THEY HAVE A BIG PROBLEM WITH SPATIAL PATTERN SEPARATION. TOGETHER WITH TIM AT CAMBRIDGE UNIVERSITY, WE DELIVERED A TOUCH SCREEN SYSTEM TO EVALUATE FACIAL PATTERN SEPARATION. WHAT WE DO, FIRST WE JUST -- IT'S A FOOD REWARD BASED SYSTEM. FIRST, WE JUST PUT ONE LID ICON IN THE SCREEN AND TEACH THE MOUSE IF IT TOUCHES THE LID ICON WITH ITS NOSE, IT WILL GET A FOOD REWARD. WE PUT TWO LID OBJECTS ON AND TRAIN IT THAT IT WILL ONLY GET A FOOD REWARD IF IT TOUCHES THE LEFT ONE, NOT THE RIGHT ONE. THEN WE DECREASE THE DISTANCE BETWEEN THE TWO LID OBJECTS. AND AS YOU DECREASE THE DISTANCE, THE ANIMAL WILL MAKE MORE ERRORS. RUNNERS MAKE FEWER ERRORS THAN DO SEDANTRY MICE, STRONGLY CORRELATED WITH THE EFFECTIVE RUNNING ON NEURO GENESIS. WE FOUND MANY YEARS AGO, TEN YEARS AGO, THAT IF WE SUBJECT MICE OR RATS TO AN INTERMITTENT FASTING DIET WHERE ON ALTERNATE DAYS THEY FAST FOR 24 HOURS, THAT ALSO SIMILAR TO EXERCISE, WILL INCREASE NEURO GENESIS. AND THEN WE PUBLISHED SEVERAL PAPERS ON THAT. MORE RECENTLY, ALEXIS, A GRADUATE STUDENT IN MY LAB AT PRINCEN, SHE HAD A COMEANT -- I COMENTORED HER. IN THIS NATURE NEUROSCIENCE STUDY SHE SHOWED THAT DIABETES, DB/DB MICE. WHEN YOU EAT A MEAL, LEPTIN IS RELEASED INTO YOUR BLOOD AND GOES TO YOUR BRAIN AND TELLS YOU TO STOP EATING. IF YOU HAVE A MUTATION IN THE LEPTIN RECEPTOR. YOU DON'T STOP EATING. THESE MICE DON'T STOP EATING AND THEY BECOME OBESE AND DIABETIC. AND ALEXIS FOUND THAT DIABETIC MICE HAVE IMPAIRED NEURO GENESIS, IMPAIRED SYNAPTIC PLASTICITY. AND IMPAIRED LEARNING AND MEMORY, HIPPOCAMPUS DEPENDENT. SO IN THIS STUDY I'M SHOWING YOU ONE SLIDE. IT WAS PUBLISHED IN THIS JOURNAL HIPPO CAMPINGS. ESSENTIALLY SHE TOOK WILDTYPE MICE, DIABETIC MICE, AND SHE PUT RUNNING WHEELS IN THEIR CAGES OR NOT, SHE PUT THEM ON A DID ITRY ENERGY RESTRICTION DIET OR NOT, AND HAD ONE GROUP SHE COMBINED RUNNING WITH DIETARY ENERGY RESTRICTION. AND IS THEY DID A METHOD CALLED GOLD G STAINING. COUNTED NUMBERS OF SYNAPSES OR POST SYNAPTIC SPINES ON THESE DENDRITES OF THE HIPPO CAMPBELL DENTIA GIRUS NEURONS. THESE ARE CRITICAL FOR THE SPATIAL PATTERN SEPARATION. IF WE LOOK IN THE WILDTYPE MICE, BOTH CALORIE RESTRICTION AND RUNNING -- THIS IS OVER A PERIOD OF NINE MONTHS. SO IT'S NOT HAPPENING INSTAN TANINOUSLY. OVER NINE MONTHS THERE IS ALMOST A DOUBLING OF THE NUMBER OF SYNAPSES IN THE CALORIE RESTRICTED RUNNING MICE. IF YOU COMBINE RUNNING WITH CALORIE RESTRICTION, THERE IS APPROXIMATELY AN ADDITIVE EFFECT IN INCREASING THE NUMBER OF SYNAPSES. DIABETIC MICE, OVER ALL, GREATLY REDUCED NUMBER OF SYNAPSES, HOWEVER, BOTH CALORIE RESTRICTION AND RUNNING SIGNIFICANTLY INCREASE THE NUMBER OF SYNAPSES. IF WE LOOK DOWN HERE, IN THE SAME STUDY, SHE MEASURED BDNF LEVELS. REMEMBER, I TOLD YOU IT'S IMPORTANT FOR LEARNING AND MEMORY IN NEURO GENESIS. FOUND THAT BOTH CALORIE RESTRICTION AND RUNNING INCREASED BDNF LEVELS, AND THE COMBINATION OR THE CONSIDERABLY IMCREASE IN BDNF LEVELS. BOTTOM LINE, THERE IS A CORRELATION BETWEEN THE EFFECTS OF EXERCISE AND ENERGY RESTRICTION ON BDNF LEVELS, AND THE EFFECTS ON NUMBER OF SYNAPSES. AGAIN, ABOUT TEN YEARS AGO, IN COLLABORATION WITH FRANK, UC IRVINE WHO DID MOST OF THIS WORK, WE TELEPHONED A INVOLVE MOUSE -- DEVELOPED A NOVEL MOUSE MODEL. IT WAS PUBLISHED IN THIS PAPER IN NEURON. I WON'T GO THROUGH THE DETAILS BUT THE BOTTOM LINE, THESE MICE HAVE MUTATIONS IN THREE DIFFERENT -- THEY'RE TRANSGENIC FOR THREE DIFFERENT HUMAN JEANS THAT CAUSE FAMILIAL ALZHEIMER'S DISEASE, PRECURSOR JEAN, AND THE OUTSIDE LIMITATION IN THE. TOW GENE, WHICH CAUSED A DEMENTIA DISORDER. AND POST-DOC IN MY LAB, HE TOOK THESE MICE AND HE PUT THEM ON THREE DIFFERENT -- DIVIDED THEM INTO GROUPS, THREE DIFFERENT DIETARY GROUPS. NORMAL DIET, FASTING DIET OR DAILY REDUCTION OF 30%. AND THEN A YEAR LATER, HE TESTED THEIR LEARNING AND MEMORY. AND THE BOTTOM LINE IS THAT THESE TRIPLE MUTANT ALZHEIMER'S MICE ON THE AD LIB DIET HAVE A SHALLOW LEARNING CURVE COMPARED TO THE ALZHEIMER'S MICE ON INTERMITTENT FACING OR DAILY CALORIE RESTRICTION, PERFORMED ABOUT THE SAME AS NON ALZHEIMER'S MICE. SO THESE ENERGY RESTRICTION DIETS AMEALULATED THEEARNING AND MEMORY DEFICITS. SO IN ALZHEIMER'S DISEASE THERE IS A BENEFIT OF ENERGY RESTRICTION DIETS. I'M GOING TO BRIEFLY TALK ABOUT PARKINSON'S DISEASE. DR. GOLDSTEIN IS GOING TO TALK MORE ABOUT DISORDERS, PARKINSON'S DISEASE AND RELATED MOTOR DISORDERS IN HIS TALK. IN PARKINSON'S DISEASE IT TURNS OUT THAT BEFORE NEURONS IN THE BASAL -- THE [INDISCERNIBLE] REGENERATE, RESPONSIBLE FOR MOST OF THE MOTOR SYMPTOMS. BEFORE THAT HAPPENS, THERE IS PROBLEMS IN THE BRAIN STEM. THERE IS PATHOLOGY, DEGENERATION OCCURRING IN THE BRAIN STEM BEFORE THE SUBJECT STANIA ANYTHINGRA. THERE IS A CLINICAL HISTORY OF CHRONIC CONSTIPATION OR OTHER NERVOUS SYSTEM PROBLEMS BECAUSE OF PROBLEMS IN THE BRAIN STEM. WE DID A STUDY RECENTLY PUBLISHED AND WHAT THEY DID IS THEY TOOK MICE THAT EXPRESSED A HUMAN ALPHA MUTATION THAT CAUSES PARKINSON'S DISEASE. IT'S EXPRESSED UNDER THE CONTROL OF A NEURON SPECIFIC PROMOTER. TURNS OUT THEY HAVE A LOT OF BRAIN STEM PATHOLOGY. SO WE PUT TRANSMITTERS IN THE ANIMAL SO WE COULD MONITOR THEIR HEART RATE CONTINUOUSLY. AS YOU KNOW, THE NERVOUS SYSTEM CONTROLS HEART RATE. AND SO THE WAY TO -- THEN SHE HAD THESE MICE ON THREE DIFFERENT DIETS. NORMAL DIET, AD LIB FEEDING, ALTERNATE FASTING DIET, OR A McDONALD DIET. HIGH CALORIE, FRUCTOSE IN THEIR WATER. AND SHE THEN MEASURED HEART RATE PRIOR TO INITIATION OF THE DIET SO THAT'S SHOWN HERE. THE DASHED LINES ARE THE PARKINSON'S DISEASE MICE, THE SOLID ARE THE WILDTYPE MICE. SHE FOUND A SMALL BUT STICKILY STICKILY -- SIGNIFICANTLY SIGNIFICANT ELEVATED HEART RATE, BEFORE THEY DEVELOPED MOTOR SIGNS. SHE PUT THEM ON A DIET AND 4, 8, 12 WEEKS LATER. THE RED IS THE ALTERNATE DAY FASTING DIET. THE BLACK IS A NORMAL DIET. THE BLUE IS THE McDONALD'S DIET. AND SO WHAT SHE FINDS, EVEN WITHIN A MONTH, THE ALTERNATE FASTING DAY DIET, ANIMALS HAVE LOWERED RESTING HEART RATE, HIGHLY SIGNIFICANT EFFECT. THAT WAS TRUE IN BOTH THE WILDTYPE AND PARKINSON'S DISEASE MICE. OKAY? THE McDONALD'S DIET, PARKINSON'S MICE HAVE THE HIGHEST RESTING HEART RATE. AND MORE THAN THE WILDTYPE. AND THEN THESE SEPARATION IN THESE DIETARY EFFECTS INCREASES AS THE ANIMALS GET OLDER. AT 1 WEEKS OF AGE IT'S -- 12 WEEKS OF AGE IT'S STILL PRIOR TO ONSET OF MOTOR DYSFUNCTION IN THE PARKINSON'S DISEASE MICE. I'M NOT GOING TO SHOW YOU BUT WE DID OTHER MANIPULATIONS USING ATTRO PINE, COLIN EDGIC ANTAGONISTS AND BETA BLOCKER. THE BOTTOM LINE SUGGESTS THAT THESE PARKINSON'S MICE HAVE A DEFICIT IN COLONUDGEN DRIVE TO THE HEART THAT LEADS TO AN ELEVATION IN RESTING HEART RATE. WE THINKS IT IS A PROBLEM WITH THE [INAUDIBLE]. THEY MAY HAVE SYMP THAT PETIC PROBLEMS THAT DR. GOLDSTEIN WILL ADDRESS. INTERMITTENT DIET, EXERCISE, ENGAGINGEN AN INTELLECTUAL TASK CAUSES MILD STRESS. THEY UPREGULATE NEUROTROPIC FACTORS, PROTEIN CHAPERONES I DIDN'T SHOW YOU. ENZYMES, AND ALSO INTERESTINGRY, PGC1 ALPHA, A TRANSCRIPTION FACTOR CRITICAL FOR MITOCONCREE ALBIOGENESIS, THE PROLIFERATION CAN BE INDUCED BY ENERGETIC STRESS. SO IN MUMP CELLS -- MUSCLE CELLS, INCREASES MITOCONCREIAL BIOGENESIS AND ADAPTIVE RESPONSES TO EXERCISE. AND IN A PAPER THAT JUST CAME OUT IN NATURE COMMUNICATIONS, WE'VE SHOWN THAT PGC1 ALPHA IS CRITICAL FOR INCREASE IN PRODUCTION OF MITOCHONDRIAL NEURONS DURING THEIR DEVELOPMENT. SO RED IS MITOCHONDRIA. THIS INCREASE. THIS IS THREE DAYS IN CULTURE, TEN DAYS IN CULTURE. AS THEY GROW, MITOCHONDRIA INCREASE IN NUMBER. THEY MOVE INTO THE DENDRITES. WERE ABLE TO KNOCK DOWN OR OVEREXPRESS PGC1 ALPHA, USING ADENOVIRAL VECTORS. WE FIND WHEN WE KNOCK DOWN PGC1 ALPHA, WE DECREASE THE NUMBER OF DENDRITIC SPINES, THE NUMBER OF SYNAPSES COMPARED TO NEURONS INFECTED WITH CONTROL ADENOVIRUS. IF WE OVEREXPRESS, WE INCREASE THE NUMBER OF DENDRITIC SPINES. THAT'S QUANTIFIED HERE. SO KNOCK DOWN PGC1 ALPHA, THE CEASED NUMBER OF SYNAPSES, OVER EXPRESSED INCREASED. WE FOUND INVIVO, IF WE INFECT NEURONS WITH FHRNA AGAINST PCG1 ALPHA, BOTTOM LINE IS OVER TIME WE DECREASE THE NUMBER OF DENDRITIC SPINES. THAT SUGGESTIONS THAT PCG1 ALPHA AND MIDO BEYOND TREIAL BIOGENESIS ARE CRITICAL FOR THE FORMATION AND MAINTENANCE OF HIPPO CAMPBELL SYNAPSES. FINALLY, WE SHOWED THAT BDNF WILL INCREASE PGC ONE ALPHA PROMOTER ACTIVITY. THIS IS A REPORTER ASSAY IN CULTURE. AND THEN WE FOUND THAT IF WE -- BDNF WILL INCREASE THE NUMBER OF SYNAPSES IN CULTURED NEURONS. AND, HOWEVER, IF WE KNOCK DOWN PGC1 ALPHA, THE ABILITY TO INCREASE SYNAPSES IS ATTENUATED. AND THEN FINALLY, MY TIME IS ALMOST UP. SO I JUST WANT TO BRIEFLY TALK ABOUT A COUPLE FARM COLLAGICAL APPROACHES THAT MIGHT MIMMICK OR OTHERWISE -- YES, MIMIC OF THE EFFECTS OF EXERCISE OR INTERMITTENT FASTING. AND WE HAVE TWO PAPERS IN PRESS. ONE WHERE WE SUPPLEMENTED THE DIET OF ALZHEIMER'S MICE WITH NICOTIN APPLIED, 234 CREASING LEVELS IN THE CELLS. THAT HAS BENEFIT EFFICIENTLY EFFECTS IN SHOWING COGNITIVE DECLINE. WE FOUND ENHANCED BIOENERGETICS. ANOTHER PAPER, IN COLLABORATION WE SUPPLEMENTED THE DIET OF THE SAME ALZHEIMER'S MICE WITH A KETONE ESTHER, FOUND THAT BENEFICIAL EFFECTS ON THE MICE. ANOTHER EXAMPLE IS [INDISCERNIBLE] PEPTIDE 1 WHICH IS A PEPTIDE PRO TO USED BY CELLS IN YOUR GUT. INCREASES INSULIN SENSITIVITY IN MUSCLE AND LIVE CELLS. WE HAVE DEVELOPED AN ANALOG OF GLP-1 CALLED EXTENDON 4 FOR POTENTIAL USE IN ALZHEIMER'S BUT INITIALLY DEVELOPED FOR DIABETES. SO IT'S USED IN DIABETES PATIENTS. WE FIND IN ANIMAL MODELS THIS PEPTIDE WILL, THROUGH A CYCLIC INCREASE BDNF LEVELS AND HAVE BENEFICIAL EFFECTS, SO WE HAVE A CLINICAL TRIAL ONGOING IN OUR CLINICAL PROBLEM IN HARBOR HOSPITAL IN BALTIMORE THAT STARTED A YEAR-AND-A-HALF AGO, WHERE WE'RE TESTING THIS DRUG IN PATIENTS WITH MILD COGNITIVE IMPAIRMENT. FINALLY I WANT TO TALK ABOUT INTERMITTENT FASTING IN HUMANS. WE'VE DONE TWO STUDIES SHOWING THAT INTERMITTENT FASTING DIETS, EITHER EATING ONLY ONE MODERATE SIZED MEAL ON ALTERNATE DAYS OR TWO DAYS A WEEK HAVE HEALTH BENEFITS. THIS WAS A TWO MONTH STUDY IN ASTHMA PATIENTS, THIS WAS 6 MEDICINE IN WOMEN AT RISK FOR BREAST CANCER. NOW WE HAVE A TRIAL WE'RE STARTING IN SUBJECTS AT RISK FOR COGNITIVE IMPAIRMENT BECAUSE OF THEIR AGE AND BEING INSULIN RESISTANT. I'M ALMOST DONE. DON'T WANT TO TAKE TIME AWAY FROM DR. GOLDSTEIN, BUT WE'RE REALLY INTERESTED NOW IN A LOT, IN SOMETHING THAT'S BEEN KNOWN FOR A LONG TIME FOR CENTURIES, THAT FASTING SEEMS TO BE GOOD FOR HEALTH. MANY OF YOU KNOW SINCLAIR, HE PUBLISHED A BOOK CALLED "THE JUNGLE" ABOUT THE MEAT PACKING INDUSTRY. HE ALSO PUBLISHED A BOOK IN 1911 CALLED THE FASTING CURE. I'M NOT AN M.D., SO THE M.D.'S CAN CRITICIZE ME, BUT WHAT YOU KNOW TON SINCLAIR HAD IN THE PREFACE, HE INTERVIEWED 277 PEOPLE WHO HAD SOME AILMENT, THEN WENT ON A FASTING DIET. VARIABLE LENGTH AND INTERVALS. AND WHAT HE REPORTS IS THAT IN THIS NUMBER OF DESPERATE CASES, ONLY ABOUT HALF A DOZEN DEAF AND UNEXPLAINED FAILURES. BY FAILURES, THE SUBJECTS DIDN'T REPORT -- THEY REPORTED THEY DIDN'T BENEFIT FROM GOING ON THE FAST. SURELY CANNOT BE THE MEDICAL MEN AND SCIENTISTS WILL CONTINUE FOR MUCH LONGER TO CLOSE THEIR EYES TO FACTS OF SUCH VITAL SIGNIFICANCE. SO I THINK WE COULD BE GIVING PRESCRIPTIONS FOR ENERGY RESTRICTION EXERCISE THAT PATIENTS COULD FOLLOW, IF WE SIMPLY ENCOURAGE THEM. WE FOUND IN OUR TWO STUDIOS OF INTERMITTENT FASTING, ONCE THE SUBJECTS GOT BEYOND 3 WEEKS NOT ONLY WAS IT NOT DIFFICULT FOR THEM TO REMAIN IN THIS INTERMITTENT FASTING DIET BUT THEIR MOOD IMPROVED, AND THEY STAYED ON THE DIET BECAUSE THESE WERE OVERWEIGHT SUBJECTS. THEY WERE LOSING WEIGHT. THEIR HEALTH WAS IMPROVING. THEY WERE FEELING BETTER. SIMILAR TO EXERCISE REGIMENS, INTERMITTENT FASTING REGIMENS I THINK FOR MANY SUBJECTS ARE DOABLE. AND SOMETHING THAT, HOWEVER -- YOU CAN READ ABOUT THIS. THIS WAS THE LAST FIGURE IN THIS METABOLISM ARTICLE. I WANTED TO POINT OUT, NOBODY IS GOING TO MAKE ANY MONEY FROM THIS. AND SO THE FOOD INDUSTRY, OBVIOUSLY, THE PHARMACEUTICAL INDUSTRY, WILL NOT BENEFIT IF PATIENTS ARE NOT SICK. OKAY. SO I'M PROPOSING THESE -- WHAT I'M CALLING -- WE NEED TO FOCUS, AT THE NIH, WE CAN DO THIS, GET IT INTO THE MEDICAL CURRICULUM. WE NEED THESE WHAT I'M CALLING PRICELESS PRESCRIPTIONS. THANK YOU VERY MUCH. [APPLAUSE] >> A COUPLE QUESTIONS. WHY DON'T WE HOLD THEM UNTIL AFTER OUR NEXT SPEAKER. THANK YOU. NOW LET ME INTRODUCE OUR SECOND SPEAKER, DR. DAVID GOLDSTEIN. CHIEF OF THE CLINICAL NEURO CARDIOLOGY SECTION AND CLINICAL NEURO SCIENTISTS PROGRAM AT NINDS. HE RECEIVED A COMBINED M.D. Ph.D. IN BEHAVIORAL SCIENCE FROM JOHNS HOPKINS IN 1976. AND HOUSE STAFF TRAINING AT THE UNIVERSITY OF WASHINGTON IN INTERNAL MEDICINE. HE CAME TO THE NIH IN 1978, OBTAINED TENOR IN NHLBI AND TRANSFERRED TO NINDS IN 1990. IN 1999 HE FOUNDED AND HAS SINCE LED THE CLINICAL NEURO CARDIOLOGY SECTION WITHIN N I HAVE NDS, A SENIOR INVESTIGATOR. HE'S RECEIVED TWO NINDS MERIT AWARDS, THE PRESIDENTIAL EXECUTIVE DIRECTOR'S AWARD FOR NATIONAL [INDISCERNIBLE] RESEARCH FOUNDATION, THE PIONEER AWARD OF THE BACK IN HEART BRAIN FOUNDATION, THE VILEM MEDAL OF THE CHECK ACADEMY OF SCIENTISTS AND THE NIH DISTINGUISHED CLINICAL TEACHER AWARD. THIS CURRENT RESEARCH FOCUSES ON BIOMARKERS AND MECHANISMS OF LOSS OF [INDISCERNIBLE] NEURONS IN PARKINSON'S DISEASE AND RELATED DISORDERS. LET'S WELCOME DR. GOLDSTEIN. [APPLAUSE] >> THANKS FOR THE INTRODUCTION. WILLY SUTTON WAS A FAMOUS AMERICAN BANK ROBBER. NOT FAMOUS FOR BEING A BANK ROBBER. HE'S FAMOUS FOR SOMETHING THAT IT'S THOUGHT HE SAID. ACCORDING TO THE STORY, HE WAS INTERVIEWED IN PRISON. AND HE WAS ASKED WHY DO YOU ROB BANKS? AND HIS ANSWER WAS BECAUSE THAT'S WHERE THE MONEY IS. AND THIS BECAME IN MEDICAL CIRCLES, SUTTON'S LAW. YOU CONSIDER THE OBVIOUS FIRST. YOU GO WHERE THE MONEY IS. WELL, WHEN IT COMES TO THE MATH GENESIS OF -- PATHOGENESIS OF PARKINSON'S DISEASE, THE MONEY IS IN THE CATA COLAMINES. THIS IS A SUBSTANTIAL NIGRA HERE. AND IT WAS -- IT'S CLASSIC FINDING IN PATHOLOGY, THE NEURO PATHOLOGY, THAT IN PARKINSON'S DISEASE, THERE IS A DEPIGMENTATION OF THE SUBJECT STANIA NIGRA. WHAT DOES THIS HAVE TO DO WITH CATTY COLAMINES? I'M DISTRIBUTING THESE VIALS, THIS IS DOPAMINE. IN SOLUTION. THIS IS ANOTHER ONE. IT'S BEEN ON MY DESK FOR SEVERAL YEARS. ALL THE WATER HAS EVAPORATED. BUT I THINK YOU CAN SEE AT THE BOTTOM, OBVIOUS BLACK PIGMENT. OR SUBSTANIA NIGRA. THE REASON FOR THE DEPIGMENTATION OF THE SUBJECT STANIA NIGRA IN PARKINSON'S DISEASE IS BECAUSE OF LOSS OF DOPAMINE NEURONS. AND YOU SEE THE STRIKING RESEMBLANCE BETWEEN THE DOPAMINE AND THE BLACK PIGMENT IN THE SUBSTANIA NIGRA. NOW, THE LOSS OF CATA COLAMINES IN PARKINSON'S DISEASE DOESN'T APPLY ONLY IN THE SUBSTANIA ANYTHINGGRA, BUT ALSO IN THE SYMPATHETIC SYSTEM IN THE HEART. THIS SHOWS [INAUDIBLE] IN THE EPICARDIAL NEVADA OF THE HEART. YOU SEE -- NERVE OF THE HEART. YOU SEE REMARKABLE ABSENCE OF THAT STAINING INDICATING A DRAMATIC LOSS OF EPEN EPEN IN YOUR RELATIONS, LIKE DOMEAMINE'S SON IN THE FAMILY. SO THE GENERAL IDEA BEHIND THIS TALK IS IF WE KNEW WHAT CAUSED THE LOSS OF CAT ACHOLIA MEAN NEURONS IN PARKINSON'S DISEASE, THIS WOULD LEAD TO NEW WAYS TO TREAT OR PREVENT THE DISEASE. NOW, THERE IS ANOTHER FINDING IN PARKINSON'S DISEASE, LEWY BODY. THESE ARE IN THE IN YOUR RELATIONS -- NEURONS, CHARACTERISTIC OF PARKINSON'S AND A SMALL FAMILY OF OTHER DISEASES. IN 1997, WAS FOUND THEY CONTAIN ABUNDANT ALPHA-SYNUCLIEN. NO ONE KNOWS EXACTLY WHAT IT DOES BUT IT'S THOUGHT THAT IT SOMEHOW CONTRIBUTES TO PARKINSON SO WE HAVE THE NEURO CHEMICAL FINDING, THE LOSS OF DOPAMINE, AND WE HAVE THE NEURO PATH LOGIC FINDING, THE LEWY BODIES IN MONOAMNUDGIC NEURONS. ONLY THE LAST SEVERAL YEARS THE IDEA HAVE EVOLVED OF A FAMILY OF THESE, THE MOST FAMOUS OF WHICH IS PARKINSON'S DISEASE. THERE IS A RARE DISEASE CALLED PURE AUTO NOMIC FAILURE. THE PATIENTS DON'T HAVE PARKINSON'S DISEASE. MY TALK TODAY, I'M GOING TO BE ADDRESSING FOUR STRAIGHT FORWARD BUT VERY DIFFICULT QUESTIONS. FIRST, ONLY A VERY MAUL% OF NEURONS ARE CATA COLA MA MERGIC. WHY ARE THEY LOST IN PARKINSON'S DISEASE. THE SECOND, HOW DO GENERAL ICED ABNORMALITIES LEAD TO SPECIFIC LOSS OF CATA COLAMINE NEURONS? THIRD, WHY DOES ALPHA SIN NUCLEIEN TEND TO SUPPORT IN -- AND FOURTH, WHY DOES IT TAKE SO MANY YEARS TO KILL OFF THE NEURONS SO THAT PARKINSON'S DISEASE IS MAINLY A JER I CAN'T CARETRIC DISEASE. TO CONVEY THE ANSWERS I'M GOING TO REFER TO WILLY SUTTON'S GETAWAY CAR. SUPPOSE YOU'RE A BANK ROBBER AND YOUR GETAWAY CAR IS IDOLING AT THE CURB. WHY IS IT IN IDOL? BECAUSE IT'S A GETAWAY CAR. YOU DON'T HAVE TIME TO TURN ON THE IGNITION. YOU HAVE TO GET AWAY WHEN THE TIME COMES. OBVIOUS ADVANTAGE TO HAVING A GETAWAY CARGOEDALING. BUT THERE IS A COST. IF YOU -- IDLING. BUT THERE IS A COST. IF YOU WAIT LONG ENOUGH, ESPECIALLY IF THERE ARE DESIGN FLAWS AND MANUFACTURING DEFECTS, EVENTUALLY THAT ENGINE IS GOING TO FAIL. AND IF YOU WERE TO DO A POSTMORTEM ON THAT ENGINE, CHANCES ARE YOU WOULD FIND ENGINE DEPOSITS, GUNK. NO AMOUNT OF ANALYSIS OF THE GUNK WOULD REALLY TELL YOU EXACTLY WHAT ORIGINALLY CAUSED THE ENGINE TO FAIL. I'M NOT AN AUTOMOTIVE ENGINEER, BUT HERE IS AN IDEA HOW THIS HAPPENS. ENERGY CONVERTS ENERGY TO MOVEMENT. YOU HAVE A CONTROLLER, THE DRIVER, THAT DETERMINES WHETHER THE CAR IS IN DRIVE OR IN PARK. AND THEN YOU HAVE GOT YOUR OIL THAT LUBRICATES THE PISTONS. AND YOU HAVE GOT WASTE MANAGEMENT. IN PARTICULAR, COMBUSTION PRODUCTS ARE TOXIC BUT THEY'RE CONVERTED TO NON TOXIC WASTE BY WAY OF A CATALYTIC CONVERTER, AND THE NON TOXIC PRODUCTS COME OUT THE TAIL PIPE. I DON'T REALLY KNOW IF THIS HAPPENS, BUT LET'S JUST SAY IT DOES. THE WAY THIS ENGINE WORKS IS THAT THERE IS A LOT OF FUEL, ACTUALLY, ENTERING THE COMBUSTION CHAMBER. BUT IT'S RECYCLED, VERY EFFICIENTLY UNDER IDOLING CONDITIONS BY SOME SORT OF FUEL RECOVERY PROCESS. SO THAT WHEN IT'S TIME TO GET AWAY, ALL THAT HAPPENS IS THAT THE FUEL RECOVERY IS BLOCKED. AND YOU'RE LEFT WITH FLOODING THE ENGINE. AND THAT'S HOW YOU'RE ABLE TO GET AWAY. LET'S JUST SAY THAT'S THE CASE. NOW, ONE WAY THAT THE ENGINE COULD FAIL EVENTUALLY WOULD BE FROM A FAULTY CATALYTIC CONVERTER. WHEN YOU'RE MAKING THIS TOXIC WASTE, IT ACCUMULATES. THAT WILL KILL THE ENGINE. ANOTHER WAY YOU COULD -- THE ENGINE COULD FAIL WOULD BE FROM FAULTY RECYCLING OF THE FUEL. FAULTY FUEL RECOVERY THAT WOULD AUGMENT THE AMOUNT OF COMBUSTION AND INCREASE THE AMOUNT OF TOXIC WASTE FORMATION. I DON'T KNOW TOO MUCH MORE ABOUT NEURO TRANSMISSION AS I DO ABOUT AUTOMOTIVE TRANSMISSION. BUT LET'S JUST EXTEND THE ANALOGY HERE. NEURONS CONVERT ENERGY TO MOVEMENT. AND HERE, HERE IS WHERE CATA COLAMINE NEURONS ARE DIFFERENT. CAT ACHOLIA MEAN NEURONS ARE LIKE A GETAWAY CAR. ON ALL THE TIME. NOW WHEN I SAY ON ALL THE TIME, THERE IS ONGOING LEAKAGE OF CAT ACHOLIA MEANS FROM STORAGE SITES IN THE THE CYTOPLASM. A CERTAIN AMOUNT GETS COMBUSTED ALL THE TIME. OXIDIZED. BY OXIDASE A, MAOA IS PRESENT IN THE OUTER MIKO CHONDRIAL MEM BRAIN. AND IT FORMS DOPAL. IT'S CONVERTED TO DOPIC. ENZYMES ARE CATALYTIC CONVERTERS. DOPAL AS ALL INTRACELLULARLY FORMED ALDA HIDES, IS TOXIC. WHAT IS THE EVIDENCE THAT THERE IS A BUILDUP OF THIS TOXIC ALD HIDE IN PARKINSON'S DISEASE. THE PU -- PUTE TAMPON -- SO THERE IS A BUILDUP OF THIS TOXIC ALD HIDE. WHY WOULD THIS BE? ONE POSSIBILITY COULD BE BECAUSE OF DEFICIENT RECYCLING. DECREASED ACTIVITY OF THE [INDISCERNIBLE] TRANSPORTER. WE DEVELOPED A WAY TO MEASURE ACTIVITY OF THE TRANSPORTER IN THE SYMPATHETIC NERVES IN THE HEART. REMEMBER, THERE IS JUST AS MUCH OF A LOSS OF NERVES IN THE HEART IN PARKINSON'S DISEASE AS THERE IS A LOSS OF DOPAMINE IN THE NIGRA SYSTEM. WHAT WE FOUND IS THAT THE -- THIS INDEX OF UPTAKE IS INCREASED IN LEWY BODY DISEASES TOWARD TO ATROPHY WHERE THERE IS NO EVIDENCE OF DECREASE IN UPTAKE. REMEMBER, MULTIPLE SYSTEM ATROPHY IS A [INDISCERNIBLE] BUT WHERE IT'S DEPOSITED IN APOLOGIAL CELLS -- APOLOGYIAL CELLS, NOT NEURONS. SO WE DEVELOPED A METHOD TO MEASURE ALDEHYDE DEHYDROGENASE ACTIVITY, LOOKING AT THE RATIO OF DOPAL TO DOPIC. IN PATIENTS WITH PARKINSON'S DISEASE. THIS IS WHAT WE FOUND. THE RATIO IS HIGHLY SIGNIFICANTLY DECREASED IN THE PUT -- PUTT AMEN OF PARKINSON'S DISEASE. WHAT ABOUT ALPHA [INDISCERNIBLE]. IN THIS ANALYSIS, IT'S LIKE THE OIL LUBRICATING THE PISTONS. NORMALLY, IT'S DISSOLVED IN THE CYTOSOL, BUT IT'S PRECIPITATED. IN LEWY BODIES. IMPORTANTLY, A DOPAL [INDISCERNIBLE] AND POLIMS ARES. THAT IS, THIS TOXIC BYPRODUCT BUILDS UP GUNK. IN THE GETAWAY CAR ENGINE. SO FOR INSTANCE, HERE YOU CAN SEE THAT DIMER TRIMER TETROMUSLIMERS AND -- TETRAMERS BUILD UP WHEN IT'S EXPOSED TO DOPAL, AS OPPOSED TO DOMEAMINE OR THE NON TOXIC DOPIC. HERE YOU SEE AN ACTUAL PARTICIPATION OF THE ALPHA SIGN IN YOUICALLIEN BY DOPAL. IN THE LAST PART OF THE TALK I WANT TO DEAL WITH WHY PARKINSON'S DISEASE IS OF OLD PEOPLE. TO CONVEY THE IDEA, I NEED TO TEACH ABOUT TWO CONCEPTS OF SCIENTIFIC INTEGRATIVE MEDICINE. ALSTATIC LOAD AND COMPENSATOR ACTIVATION. IF YOU THINK ABOUT THE HEATING SYSTEM IN YOUR HOUSE, YOU'VE GOT A NEGATIVE FEEDBACK LOOP. THE TEMPERATURE OF THE HOUSE GOES DOWN, THERE IS A DISCREPANCY BETWEEN THE INSIDE TEMPERATURE AND THE THERMOSTAT SETTING AND THE SIGNAL DRIVES THE FURNACE. THE FURNACE GENERATES HEAT AND THE TEMPERATURE GOES UP, A CLASSICAL NEGATIVE FEEDBACK LOOP. WHEN YOU HAVE A NEGATIVE FEEDBACK LOOP IT CAN BE SHOWN MATHEMATICALLY THAT THE LEVEL OF THE MONITORED VARIABLE, IN THIS CASE, THE TEMPERATURE, ALWAYS REACHES A STEADY STATE. MAY NOT BE THE SET TEMPERATURE BUT IT WILL BE CONSTANT. ALOE STATIC LOAD REFERS TO CHRONIC WEAR AND TEAR. IN ESSENCE, AS THE FURNACE IS ON, THERE IS WEAR AND TEAR ON THE FURNACE, ESPECIALLY IF THERE ARE MANUFACTURING FLAWS OR DESIGN FLAWS. AS THE NEURONES IS ON MORE -- FURNACE IS ON MORE IT'S LESS EFFICIENT. IF IT'S LESS EFFICIENT, IT'S GOING TO BE ON MORE OF THE TIME BECAUSE OF ITS NEGATIVE FEEDBACK LOOP. IF IT'S ON MORE OF THE TIME, THEN IT'S GOING TO BE MORE WEAR AND TEAR. THERE IS MORE WEAR AND TEAR, IT WILL BECOME LESS EFFICIENT. NOW YOU HAVE A POSITIVE FEEDBACK LOOP. ONCE YOU HAVE A POSITIVE FEEDBACK LOOP, THIS IS AN INHERENTLY UNSTABLE SITUATION. AND THE SYSTEM IS GOING TO BE DESTROYED. AND YOU CAN MODEL WHAT HAPPENS TO A NEURON IN THE SETTING OF ALOSTATIC LOAD, BECAUSE OF THE WEAR AND TEAR AND DECREASED EFFICIENCY AFTER A CERTAIN PERIOD OF TIME, THERE IS A RAPID FALL IN FUNCTIONAL CAPACITY. IN PARKINSON'S DISEASE, MOST OF THE NEURONS HAVE TO ALREADY -- OR TERMINALS HAVE TO BE GONE FOR THE PERSON TO HAVE SYMPTOMS. BY THEN, IT'S TOO LATE TO REALLY DO ANYTHING IN TERMS OF EFFECTIVE TREATMENT. WHEN YOU HAVE A DESIGN FLAW, SUCH AS GENETIC DEFECT IN THE ALPHA SIN NUCLEIIAN GENE, THAT SHIFT TO THE LEFT THE CURVE SO YOU END UP WITH A SYMPTOMATIC DISEASE AT A YOUNG AGE. THERE ARE A VARIETY OF LOOPS THAT APPLY IN PARKINSON'S DISEASE. I'M JUST LOOKING AT ONE. YOU HAVE A POSITIVE FEEDBACK LOOP FROM ALL THE SIGNS IN THE LOOP ARE POSITIVE. SO IN THIS CASE, THE ONGOING LEAKAGE OF INTO THE CYTOPLAS. RESULTS IN THE PRODUCTION OF DOPAL. DOPAL PRODUCES SIN NUCLEONAPTHY. IT MAY INTERFERE WITH THE VMAT THAT'S GOING TO AUGMENT THE LEAK. YOU HAVE A POSITIVE FEEDBACK LOOP. YOU LOOK AT THE DIAGRAM, THERE ARE MULTIPLE FEEDBACK LOOPS THAT ARE POSSIBLE THAT INVOLVE DOPAL. WELL, FINALLY, WHAT DO WE DO IN TERMS OF NEW IDEAS ABOUT TREATMENT OR PREVENTION BASED ON THE GETAWAY CAR ANALOGY? WELL, THE CAR HAS TO BE IDOLING. WHO SAYS IT HAS TO BE IDLING AT A HIGH RATE? IT COULD BE IDLING AT A LOW RATE. DROP THE IDLE RATE. OR YOU NEED THE CATALYTIC CONVERTER IF THERE IS SOME PRODUCT OF THE DEGENERATIVE PROCESS THAT INTERFERES WITH THAT CATALYTIC CONVERTER, DO SOMETHING THAT WILL DECREASE FAILING OF THE CATALYTIC CONVERTER. YOU WANT TO DECREASE THE BUILDUP OF GUNK EVENTUALLY, THAT GUNK BUILDUP WILL BE SUFFICIENT OF ITSELF, INTERFERE WITH THE FUNCTION OF THE ENGINE. YOU'D WANT TO INCREASE THE EFFICIENCY OF THE FUEL RECYCLING. THIS IS A DIAGRAM OF THESE DIFFERENT POTENTIAL PLACES WHERE EARLY TREATMENT IN A PRESYMPTOMATIC PHASE COULD PREVENT THE DISEASE FROM DEVELOPING UNTIL THE PERSON WAS A RIPE OLD AGE ANYWAY. FOR INSTANCE, YOU CAN INHIBIT MONOMEAN OXIDASE. THAT WILL DECREASE DOPAL FORMATION. REACTIVE OXYGEN SPECIES BY WAY OF LIPID [INDISCERNIBLE] WHICH DR. MATSSON IS AN EXPERT ON, THIS RESULTS IN INHIBITION OF [INDISCERNIBLE]. FAILING OF THE CATALYTIC CONVERTER. DO SOMETHING THAT INTERFERES WITH THE FORMATION OF THE REACTIVE OXYGEN SPECIES OR THE LIPID PER OXIDATION OR THE EFFECT ON [INDISCERNIBLE]. OR IF ALPHA SIN NUCLEIIANOPATHY, ESPECIALLY IF THEY'RE SIGNIFICANT, DO SOMETHING THAT INTERFERES WITH THE PROTEIN CROSS LINKING EXERTED BY DOPAL. OR SINCE THIS IS THE MAIN DETERMINANT OF THE CYTOPLASTMIC DOPAMINE CONCENTRATION, IS THERE A WAY TO INCREASE THE EFFICIENCY OF VM. AT2. -- VMAT2. THE LAST TOPIC HAS TO DO WITH COMPETENCITRY ACTIVATION. THIS MEANS WHEN WOULD YOU START TREATMENT? OF SOMEBODY WHO DOESN'T HAVE SYMPTOMS OF A DISEASE? ALL DRUGS ARE GOING TO HAVE SIDE EFFECTS. BUT IF YOU WAIT UNTIL THE PERSON HAS SYMPTOMS IT'S TOO LATE. SO HOW DO YOU CONCEPTUALLY -- HOW DO YOU FIGURE OUT WHEN TO TIME THE START OF TREATMENT? IF YOU THINK ABOUT THE HEATING SYSTEM IN YOUR HOUSE, LET'S SAY YOU HAVE A FURNACE AND HEAT PUMP. THE FURNACE IS THE MAIN THING. THE HEAT PUMP IS A BACKUP. HOW WOULD YOU KNOW WHEN THE FURNACE EFFICIENCY, THE FURNACE FUNCTION, IS DEGENERATING? WOULD YOU MONITOR THE TEMPERATURE IN YOUR HOUSE? NO. BY THE TIME THE TEMPERATURE IN THE HOUSE GOES DOWN, THE ENTIRE HVAC SYSTEM HAS BEEN DESTROYED. WHAT YOU WOULD MONITOR WOULD BE ACTIVITY OF THE HEAT PUMP. AS THE FURNACE EFFICIENCY IS DECREASING, THE HEAT PUMP GETS TURNED ON MORE. YOU'RE ABLE TO REGULATE THE TEMPERATURE IN THE HOUSE. AND YOU USE THE COMP PENCETRY ACTIVATION OF THE HEAT PUMP WHEN IT'S TIME TO -- [INAUDIBLE] THERE IS A COMPETENCITRY INCREASE TO THE REMAINING TRAFFIC IN THE REMAINING TERMINALS. NOW YOU KNOW WHEN TO START TREATMENT. YOU WOULD START TREATMENT WHEN YOU HAVE REACHED YOUR PEEK SLOPE OF COMPENCETRY ACTIVATION. COMING UP WITH WAYS TO MEASURE COMP PENCETRY ACT VISION OF DOPAMINE SYSTEM OR CATA COLAMINE SYSTEMS IS A CHALLENGE WE'RE WORKING ON NOW. I THINK WE HAVE AN ANSWER BUT I DON'T HAVE TIME TO GO INTO IT. SO INCONCLUSION, CATA COLAMINE NEURONS ARE LIKE THE ENGINES IN A GETAWAY CAR. THE CONTENTS ARE LEAKING CONTINUOUSLY INTO THE CYTOPLASM WHERE INZOOMATIC OXIDATION RESULTS IN ALD HIDES THAT ARE TOXIC. THE DOPAMINE NEURONS DEPEND ON THE SEQUESTRATION TO LIMIT THE TOXICITY, IF YOU YOU'LL EXCUSE A PUN, AUTO TOXICITY, THAT WAS FUNNY. THEY PROMOTE ALPHA SIN UKEICALLIENOPATHY, AND THAT MAY INCREASE CYTOPLASMIC CATECHOLAMINES. PARKINSON'S DISEASE IS A DISEASE OF THE LEARNED BECAUSE OF ALOE STATIC LOAD. HYPOTHESIS FOR THE FUTURE IS STRATEGIES THAT LIMIT DOPAL PRODUCTION OR TOXICITY COULD RETARD THE DISEASE PROCESS. I WANT TO CLOSE WITH A QUOTE FROM A FAMOUS CARDIOLOGIST NAMED THOMAS GRAY BOYS. HE HAS PARKINSON'S DISEASE WITH ORTHO STATIC HIPPO TENSION AND DEMENTIA. BUT HE WROTE A BOOK, INCREDIBLE BOOK CALLED LIFE IN THE BALANCE. AND IN THAT BOOK, HE WRITES THIS. AS A YOUNG INTERN AND RESIDENT LEADER, I WAS ACCUSTOMED TO BEING SUMMONED IN THE MIDDLE OF THE NIGHT. YOU COULD LAUNCH MYSELF OUT OF BED. GET DRESSED, AND PERFORM AT MY INTELLECTUAL PEEK WITHIN MOMENTS. I COULD MAKE LIFE AND DEATH DECISIONS WITHIN SECONDS OF A NIGHTTIME PHONE CALL. TODAY, I WAIT FOR THOUSANDS OF TINY CELLULAR ENGINES TO START THEMSELVES SO I CAN RISE FROM THE BED AND BEGIN ANOTHER DAY. SO I WANT TO ACKNOWLEDGE THE TREMENDOUS HELP OF MY TEAM AND CLINICAL NEURO CARDIOLOGY SECTION, ESPECIALLY COURTNEY HOLMES WHO IS SITTING HERE, WHO RUNS OR LABORATORY. I THANK YOU FOR YOUR ATTENTION. [APPLAUSE]