1 00:00:11,440 --> 00:00:13,640 Welcome to the Clinical Center Grand Rounds, 2 00:00:13,640 --> 00:00:17,440 a weekly series of educational lectures for physicians and 3 00:00:17,440 --> 00:00:20,080 health care professionals broadcast from the Clinical 4 00:00:20,080 --> 00:00:23,040 Center at the National Institutes of Health in 5 00:00:23,040 --> 00:00:24,840 Bethesda, MD. 6 00:00:24,840 --> 00:00:28,400 The NIH Clinical Center is the world's largest hospital totally 7 00:00:28,400 --> 00:00:32,080 dedicated to investigational research and leads the global 8 00:00:32,080 --> 00:00:35,040 effort in training today's investigators and discovering 9 00:00:35,040 --> 00:00:37,200 tomorrow's cures. 10 00:00:37,200 --> 00:00:46,000 Learn more by visiting us online at http://clinicalcenter.nih.gov 11 00:00:46,000 --> 00:00:51,800 >OUR SPEAKER IS DR. DIMA 12 00:00:51,800 --> 00:00:56,920 HAMMOUD, CENTER FOR INFECTIOUS 13 00:00:56,920 --> 00:01:00,000 DISEASE IMAGING, NIH CLINICAL 14 00:01:00,000 --> 00:01:00,920 CENTER, NATIONAL INSTITUTE OF 15 00:01:00,920 --> 00:01:03,000 ALLERGY AND INFECTIOUS DISEASE. 16 00:01:03,000 --> 00:01:05,040 DR. HAMMOUD EARNED HER MEDICAL 17 00:01:05,040 --> 00:01:08,320 DEGREE AT AMERICAN UNIVERSITY IN 18 00:01:08,320 --> 00:01:10,280 LEBANON, COMPLETED INTERNSHIP IN 19 00:01:10,280 --> 00:01:12,120 INTERNAL MEDICINE, RESIDENCY IN 20 00:01:12,120 --> 00:01:15,040 DIAGNOSTIC RADIOLOGY AT THE 21 00:01:15,040 --> 00:01:15,600 AMERICAN UNIVERSITY. 22 00:01:15,600 --> 00:01:17,240 IN 2001 SHE JOINED THE JOHNS 23 00:01:17,240 --> 00:01:21,480 HOPKINS SCHOOL OF MEDICINE AS A 24 00:01:21,480 --> 00:01:24,680 FELLOW IN RADIOLOGY, SECOND 25 00:01:24,680 --> 00:01:27,240 FELLOWSHIP IN POSITRON IMAGING, 26 00:01:27,240 --> 00:01:30,600 JOINED THE DEPARTMENT AT THE NIH 27 00:01:30,600 --> 00:01:39,280 CLINICAL CENTER IN 2006, IN 2011 28 00:01:39,280 --> 00:01:40,360 TENURE-TRACK INVESTIGATOR, 29 00:01:40,360 --> 00:01:42,000 FOCUSING ON DEVELOPMENT OF 30 00:01:42,000 --> 00:01:42,800 PRE-CLINICAL TRANSLATIONAL AND 31 00:01:42,800 --> 00:01:50,520 CLINICAL MOW MOLECULAR IMAGING, 32 00:01:50,520 --> 00:01:53,160 RELIABLE IMAGING BIOMARKERS OF 33 00:01:53,160 --> 00:01:54,480 INFECTIOUS DISEASES, TO 34 00:01:54,480 --> 00:01:55,440 UNDERSTAND PATHOPHYSIOLOGY SUCH 35 00:01:55,440 --> 00:01:57,080 AS HIV, IN THE BRAIN AND 36 00:01:57,080 --> 00:01:58,760 PERIPHERY, AS WELL AS 37 00:01:58,760 --> 00:02:01,480 DEVELOPMENT AND VALIDATION OF 38 00:02:01,480 --> 00:02:04,480 NOVEL FUNGAL INFECTIONS SPECIFIC 39 00:02:04,480 --> 00:02:07,240 IMAGING BIOMARKERS IN ANIMAL 40 00:02:07,240 --> 00:02:09,040 MODELS USING NON-INVASIVE 41 00:02:09,040 --> 00:02:12,120 TECHNIQUES, MOSTLY PET IMAGING. 42 00:02:12,120 --> 00:02:13,760 DR. HAMMOUD IS AN 43 00:02:13,760 --> 00:02:14,880 INTERNATIONALLY AND NATIONALLY 44 00:02:14,880 --> 00:02:23,400 RECOGNIZED EXPERT IN MOLECULAR 45 00:02:23,400 --> 00:02:27,200 IMAGING, WORKS IN COLLABORATION 46 00:02:27,200 --> 00:02:29,560 WITH NIAID'S BSL4 INTEGRATED 47 00:02:29,560 --> 00:02:31,200 FACILITY AT FORT DETRICK. 48 00:02:31,200 --> 00:02:33,240 SHE'S AUTHORED OVER 100 49 00:02:33,240 --> 00:02:34,880 ARTICLES, NUMEROUS BOOK CHAPTERS 50 00:02:34,880 --> 00:02:37,680 AND SERVESES CHAIR OF IMAGING 51 00:02:37,680 --> 00:02:46,080 INFECTION INTEREST GROUP OF THE 52 00:02:46,080 --> 00:02:47,480 WORLD MOLECULAR IMAGING SOCIETY. 53 00:02:47,480 --> 00:02:51,480 SHE'S BOARD CERTIFIED IN 54 00:02:51,480 --> 00:02:52,800 RADIOLOGY, ALSO STAFF 55 00:02:52,800 --> 00:02:54,360 NEURORADIOLOGY IN RADIOLOGY 56 00:02:54,360 --> 00:02:55,680 SCIENCE DEPARTMENT AT NIH 57 00:02:55,680 --> 00:02:56,280 CLINICAL CENTER. 58 00:02:56,280 --> 00:02:58,960 HER TALK TODAY IS ENTITLED THE 59 00:02:58,960 --> 00:03:00,480 PROMISE OF MOW ELECTRIC IMAGING, 60 00:03:00,480 --> 00:03:01,080 SPOTLIGHT ON CNS INFECTIONS. 61 00:03:01,080 --> 00:03:03,080 PLEASE WELCOME OUR SPEAKER, DR. 62 00:03:03,080 --> 00:03:05,760 HAMMOUD. 63 00:03:05,760 --> 00:03:08,200 >> THANK YOU FOR THE NICE 64 00:03:08,200 --> 00:03:10,280 INTRODUCTION AND FOR SHARING 65 00:03:10,280 --> 00:03:12,880 YOUR LUNCH HOUR WITH ME TODAY. 66 00:03:12,880 --> 00:03:14,360 OVER THE NEXT HOUR OR SO I'LL BE 67 00:03:14,360 --> 00:03:18,360 TALKING ABOUT SOME OF THE WORK 68 00:03:18,360 --> 00:03:21,720 WE'VE BEEN DOING CONCENTRATING 69 00:03:21,720 --> 00:03:23,320 ON USING MOLECULAR IMAGING, 70 00:03:23,320 --> 00:03:26,320 ADVANCED MR IMAGING TO TRY TO 71 00:03:26,320 --> 00:03:28,440 BETTER UNDERSTAND CNS INFECTION 72 00:03:28,440 --> 00:03:29,400 AND IMPROVE DIAGNOSTIC 73 00:03:29,400 --> 00:03:29,960 ABILITIES. 74 00:03:29,960 --> 00:03:32,440 I HAVE NO DISCLOSURES OR 75 00:03:32,440 --> 00:03:35,600 CONFLICTS OF INTEREST. 76 00:03:35,600 --> 00:03:38,560 SO, AS DR. BURKLOW SAID, I'M A 77 00:03:38,560 --> 00:03:39,840 NEURORADIOLOGIST BY TRAINING. 78 00:03:39,840 --> 00:03:45,560 WHENEVER A PATIENT PRESENTS WITH 79 00:03:45,560 --> 00:03:50,120 A SUSPECTED CNS INFECTION WE 80 00:03:50,120 --> 00:03:51,440 OBTAIN IMAGING, IMPORTANT IN 81 00:03:51,440 --> 00:03:57,440 MANAGING THE INFECTIONS. 82 00:03:57,440 --> 00:04:02,560 I USUALLY LOOK AT THOSE IMAGES 83 00:04:02,560 --> 00:04:04,320 AND TRY TO NARROW DIFFERENTIAL 84 00:04:04,320 --> 00:04:06,440 SPACE ON WHAT WE'RE SEEING, WE 85 00:04:06,440 --> 00:04:08,920 LOOK FOR THE LOCATION OF THAT 86 00:04:08,920 --> 00:04:12,720 ABNORMALITY, HOW MANY REGIONS 87 00:04:12,720 --> 00:04:16,560 ARE THERE, SYNAPSES, SOLID MASS, 88 00:04:16,560 --> 00:04:16,880 EDEMA? 89 00:04:16,880 --> 00:04:19,040 AND ALONG WITH ALL THESE 90 00:04:19,040 --> 00:04:20,280 COMBINATIONS OF FINDINGS ALONG 91 00:04:20,280 --> 00:04:22,560 WITH THE CLINICAL PICTURE WE 92 00:04:22,560 --> 00:04:23,840 USUALLY REACH A DIFFERENTIAL 93 00:04:23,840 --> 00:04:27,240 DIAGNOSIS, EVERY NOW AND THEN WE 94 00:04:27,240 --> 00:04:28,360 CAN TELL EXACTLY WHAT THE 95 00:04:28,360 --> 00:04:30,520 DISEASE IS BUT IN MOST 96 00:04:30,520 --> 00:04:32,320 SITUATIONS WE CAN'T TELL FOR 97 00:04:32,320 --> 00:04:33,920 SURE WHAT'S GOING ON. 98 00:04:33,920 --> 00:04:35,840 OR WE CANNOT DIAGNOSE FOR SURE 99 00:04:35,840 --> 00:04:37,200 WHAT'S GOING ON. 100 00:04:37,200 --> 00:04:41,920 THE OTHER ISSUE WITH 101 00:04:41,920 --> 00:04:43,000 CONVENTIONAL IMAGING, SOMETIMES 102 00:04:43,000 --> 00:04:44,240 YOU HAVE INFECTION, YOU'RE 103 00:04:44,240 --> 00:04:46,040 FOLLOWING THE PATIENT DOING 104 00:04:46,040 --> 00:04:50,080 IMAGING WITH MRI FOR EXAMPLE. 105 00:04:50,080 --> 00:04:52,640 THE QUESTION IS, IS THE PATIENT 106 00:04:52,640 --> 00:04:55,480 RECOVERING, IS THIS TISSUE? 107 00:04:55,480 --> 00:04:57,840 SOMETIMES THE RESPONSE SIZE CAN 108 00:04:57,840 --> 00:04:59,680 LAG BEHIND ACTUAL DISCOVERY. 109 00:04:59,680 --> 00:05:01,560 THE THIRD PROBLEM MANY 110 00:05:01,560 --> 00:05:05,240 INFECTIONS DON'T HAVE ANY MAJOR 111 00:05:05,240 --> 00:05:05,920 ASSOCIATED ABNORMALITIES, YET 112 00:05:05,920 --> 00:05:07,320 THE PATIENTS PRESENT WITH 113 00:05:07,320 --> 00:05:08,640 NEUROLOGIC FINDINGS, AND THE 114 00:05:08,640 --> 00:05:11,000 QUESTION IS HOW CAN WE ACTUALLY 115 00:05:11,000 --> 00:05:11,720 DOCUMENT WHAT'S HAPPENING IN THE 116 00:05:11,720 --> 00:05:14,200 BRAIN IF WE DON'T SEE ANYTHING 117 00:05:14,200 --> 00:05:15,640 ON THE SURFACE? 118 00:05:15,640 --> 00:05:19,040 AND THE ANSWER IS, YOU TRY TO 119 00:05:19,040 --> 00:05:19,960 UNDERSTAND WHAT'S HAPPENING 120 00:05:19,960 --> 00:05:23,240 UNDER THE SURFACE AND TRY TO 121 00:05:23,240 --> 00:05:23,840 IDENTIFY MOLECULAR LEVEL 122 00:05:23,840 --> 00:05:26,640 CHANGES, WHICH BRINGS US TO THE 123 00:05:26,640 --> 00:05:29,440 TOPIC OF MOLECULAR IMAGING. 124 00:05:29,440 --> 00:05:32,040 AND THIS IS A TERM THAT WAS 125 00:05:32,040 --> 00:05:34,040 COINED APPROXIMATELY TWO DECADES 126 00:05:34,040 --> 00:05:38,280 AGO TO ENCOMPASS A GROUP OF 127 00:05:38,280 --> 00:05:40,800 MODALITIES WHICH SURPASS THE 128 00:05:40,800 --> 00:05:43,000 CONVENTIONAL IMAGING TO MEASURE 129 00:05:43,000 --> 00:05:44,520 BIOLOGICAL PROCESSES AT THE 130 00:05:44,520 --> 00:05:45,360 CELLULAR AND SUBCELLULAR LEVEL 131 00:05:45,360 --> 00:05:47,080 SO WE'RE NOT JUST LOOKING AT THE 132 00:05:47,080 --> 00:05:50,240 STRUCTURE ANYMORE BUT AT THE 133 00:05:50,240 --> 00:05:51,960 BIOLOGY OF WHAT'S HAPPENING IN 134 00:05:51,960 --> 00:05:54,040 THE CELLS, WITHIN INTACT LIVING 135 00:05:54,040 --> 00:05:54,440 SUBJECTS. 136 00:05:54,440 --> 00:05:58,640 SO YOU COULD DO THAT WITH EX 137 00:05:58,640 --> 00:06:08,440 VIVO AND IN VIVO, BUT WE CAN 138 00:06:08,440 --> 00:06:10,600 STUDY BIOLOGICAL PROCESS IN 139 00:06:10,600 --> 00:06:11,800 AUTHENTIC ENVIRONMENTS. 140 00:06:11,800 --> 00:06:15,440 BUT THE ACTUAL DISCIPLINE OF 141 00:06:15,440 --> 00:06:17,440 MOLECULAR IMAGING IS NOT A 142 00:06:17,440 --> 00:06:18,240 STAND-ALONE SCIENCE. 143 00:06:18,240 --> 00:06:20,560 IT DEPENDS HEAVILY ON MANY OTHER 144 00:06:20,560 --> 00:06:21,640 DISCIPLINES AND FIELDS WITHOUT 145 00:06:21,640 --> 00:06:24,040 WHICH IT COULD NOT GROW. 146 00:06:24,040 --> 00:06:26,240 IT DEPENDS ON BASICS OF 147 00:06:26,240 --> 00:06:27,840 MOLECULAR AND CELL BIOLOGY, 148 00:06:27,840 --> 00:06:31,680 INFORMATICS, PHYSICS IS VERY 149 00:06:31,680 --> 00:06:32,360 IMPORTANT. 150 00:06:32,360 --> 00:06:34,000 ADVANCES IN NANOTECHNOLOGY, 151 00:06:34,000 --> 00:06:35,480 GENETICS, CHEMISTRY, ALL THESE 152 00:06:35,480 --> 00:06:38,240 CONSTITUTE THE BIG FIELD OF 153 00:06:38,240 --> 00:06:39,040 MOLECULAR IMAGING. 154 00:06:39,040 --> 00:06:41,640 HOWEVER, EVEN THOUGH THE TERM IS 155 00:06:41,640 --> 00:06:44,360 NEW, THE CONCEPT IS NOT THAT 156 00:06:44,360 --> 00:06:44,840 NEW. 157 00:06:44,840 --> 00:06:49,320 IN FACT, IT'S ALWAYS BEEN QUOTE/ 158 00:06:49,320 --> 00:06:49,880 UNQUOTE MOLECULAR IMAGING. 159 00:06:49,880 --> 00:06:52,440 FOR EXAMPLE, THIS IS A STUDY 160 00:06:52,440 --> 00:06:56,040 DONE IN 1965, WHERE A 161 00:06:56,040 --> 00:07:01,040 PHYSIOLOGIC CELLULAR PROCESS OF 162 00:07:01,040 --> 00:07:03,840 IDENTIFICATION IN THE FOLLICULAR 163 00:07:03,840 --> 00:07:08,120 CELL WAS CO-AUTHORED BY A SMART 164 00:07:08,120 --> 00:07:09,440 SCIENTIST, USING IODINE 131 165 00:07:09,440 --> 00:07:11,360 PRODUCED AN IMAGE OF THE THYROID 166 00:07:11,360 --> 00:07:12,880 GRAND, THAT'S NOT A STRUCTURE, 167 00:07:12,880 --> 00:07:14,200 THAT'S ACTUALLY THE FUNCTION OF 168 00:07:14,200 --> 00:07:16,760 THE IMAGE THAT IS DEPICTED ON 169 00:07:16,760 --> 00:07:17,360 THESE SCANS. 170 00:07:17,360 --> 00:07:20,200 GRANTED THEY ARE NOT REALLY GOOD 171 00:07:20,200 --> 00:07:21,400 LOOKING. 172 00:07:21,400 --> 00:07:23,320 THIS IS LINEAR SCAN, PRECURSOR 173 00:07:23,320 --> 00:07:24,640 OF THE PRECURSOR OF THE GAMMA 174 00:07:24,640 --> 00:07:26,200 CAMERA, BUT AT THAT POINT WERE 175 00:07:26,200 --> 00:07:28,760 ABLE TO ACHIEVE A FUNCTIONAL 176 00:07:28,760 --> 00:07:34,280 IMAGE, AND THAT'S THE DEFINITION 177 00:07:34,280 --> 00:07:35,160 OF MOLECULAR IMAGING. 178 00:07:35,160 --> 00:07:37,600 SINCE THEN IT'S BECOME MORE 179 00:07:37,600 --> 00:07:39,440 DIVERSE, THERE ARE MULTIPLE 180 00:07:39,440 --> 00:07:45,760 MODALITIES INCLUDED UNDER THIS 181 00:07:45,760 --> 00:07:47,320 BIG UMBRELLA. 182 00:07:47,320 --> 00:07:50,440 WE ALSO HAVE SPECIFIC TYPES OF 183 00:07:50,440 --> 00:07:58,320 MR, AS WELL OPTICAL IMAGING, 184 00:07:58,320 --> 00:08:00,840 BIOLUMINESCENCE, PHOTOACOUSTIC 185 00:08:00,840 --> 00:08:01,920 ULTRASOUND TECHNIQUES, COMPUTED 186 00:08:01,920 --> 00:08:06,240 TOMOGRAPHY, BUT TODAY I'LL FOCUS 187 00:08:06,240 --> 00:08:08,040 ON PET IMAGING, POSITRON 188 00:08:08,040 --> 00:08:09,520 EMISSION TOMOGRAPHY. 189 00:08:09,520 --> 00:08:11,080 YOU'RE FAMILIAR WITH PET, 190 00:08:11,080 --> 00:08:14,240 ESSENTIALLY TALKING ABOUT A 191 00:08:14,240 --> 00:08:21,040 RADIOACTIVE ISOTOPE, DECAYS BY 192 00:08:21,040 --> 00:08:29,760 PRODUCTION OF POSITRON, 193 00:08:29,760 --> 00:08:32,160 COLLIDES, ANNIHILATION, DETECTED 194 00:08:32,160 --> 00:08:34,240 BY OPPOSING CONSTRUCTS. 195 00:08:34,240 --> 00:08:35,360 MOST ARE RINGS SET ON THE 196 00:08:35,360 --> 00:08:36,880 PATIENT, THE MORE RINGS THE 197 00:08:36,880 --> 00:08:40,600 BIGGER THE FIELD OF VIEW YOU 198 00:08:40,600 --> 00:08:41,360 HAVE. 199 00:08:41,360 --> 00:08:42,720 THIS INFORMATION ABOUT WHERE THE 200 00:08:42,720 --> 00:08:45,840 ANNIHILATION OCCURS AND HOW MUCH 201 00:08:45,840 --> 00:08:46,920 OCCURS IS THEN TRANSLATED 202 00:08:46,920 --> 00:08:47,920 RECONSTRUCTED AND YOU END UP 203 00:08:47,920 --> 00:08:51,280 WITH AN IMAGE THAT YOU CAN LOOK 204 00:08:51,280 --> 00:08:53,000 AT, QUANTIFY, AND DIAGNOSE 205 00:08:53,000 --> 00:08:54,440 DISEASES BASED ON IT. 206 00:08:54,440 --> 00:08:56,240 AND THINGS HAVE REALLY 207 00:08:56,240 --> 00:09:03,440 PROGRESSED, IF YOU LOOK AT THE 208 00:09:03,440 --> 00:09:04,920 FIRST FDG-PET SCAN IN 1986, YOU 209 00:09:04,920 --> 00:09:08,320 IT TELL WE'VE GOTTEN FURTHER 210 00:09:08,320 --> 00:09:11,160 THANKS TO TECHNOLOGICAL ADVANCES 211 00:09:11,160 --> 00:09:12,680 MAKING MACHINES AND IMPROVING 212 00:09:12,680 --> 00:09:13,240 BIOENGINEERING. 213 00:09:13,240 --> 00:09:15,240 THAT'S WHAT MAKES PET IMAGING 214 00:09:15,240 --> 00:09:18,800 ONE OF THE HIGHEST SENSITIVITY 215 00:09:18,800 --> 00:09:23,480 TECHNIQUES IN MOLECULAR IMAGING 216 00:09:23,480 --> 00:09:30,680 WITH PICOMOLAR CONCENTRATIONS DE 217 00:09:30,680 --> 00:09:32,680 DETECTED BY PET. 218 00:09:32,680 --> 00:09:34,040 HUMAN SCANNERS ARE 45-MILLIMETER 219 00:09:34,040 --> 00:09:35,280 RESOLUTION, WHICH IS REALLY VERY 220 00:09:35,280 --> 00:09:37,280 BAD IF YOU COMPARE TO MRI FOR 221 00:09:37,280 --> 00:09:39,400 EXAMPLE BUT THESE ARE IMPROVING 222 00:09:39,400 --> 00:09:44,040 WITH ALL THE NEW ADVANCEMENTS 223 00:09:44,040 --> 00:09:45,680 WITH NEW SCANNERS, ALSO EVEN 224 00:09:45,680 --> 00:09:46,640 RADIATION EXPOSURE ASSOCIATED 225 00:09:46,640 --> 00:09:48,480 WITH PET IS BECOMING LESS AND 226 00:09:48,480 --> 00:09:49,080 LESS. 227 00:09:49,080 --> 00:09:52,640 AND THIS IS VERY IMPORTANT, FOR 228 00:09:52,640 --> 00:09:54,320 EXAMPLE, FOR PEDIATRIC IMAGING. 229 00:09:54,320 --> 00:09:59,120 ALL THIS MAKES PET IMAGING A 230 00:09:59,120 --> 00:10:00,680 VERY ATTRACTIVE MODALITY TO 231 00:10:00,680 --> 00:10:03,160 DIAGNOSE DISEASES AND TO PERFORM 232 00:10:03,160 --> 00:10:03,760 MOLECULAR IMAGING. 233 00:10:03,760 --> 00:10:06,360 AND THAT BRINGS US TO FDG, WHICH 234 00:10:06,360 --> 00:10:09,640 IS THE MOST FAMOUS AND MOST 235 00:10:09,640 --> 00:10:10,920 CLINICALLY USED MOLECULAR 236 00:10:10,920 --> 00:10:12,440 IMAGING PROBE EVER. 237 00:10:12,440 --> 00:10:17,360 AND FDG IS VERY WELL KNOWN, USED 238 00:10:17,360 --> 00:10:21,200 IN CANCER IMAGING. 239 00:10:21,200 --> 00:10:22,280 IT'S A HYDROPHILIC MOLECULE, 240 00:10:22,280 --> 00:10:24,040 NEEDS TO BE TRANSPORTED, DOES 241 00:10:24,040 --> 00:10:28,080 NOT CROSS THE BRAIN. 242 00:10:28,080 --> 00:10:29,160 TRANSPORTERS, WE HAVE A LARGE 243 00:10:29,160 --> 00:10:32,680 NUMBER OF THOSE THAT ARE 244 00:10:32,680 --> 00:10:34,960 IDENTIFIED BUT GLUT1 IS 245 00:10:34,960 --> 00:10:36,520 EXPRESSED ON MOST MAMMALIAN 246 00:10:36,520 --> 00:10:39,120 CELLS, IT HAPPENS TO NOT 247 00:10:39,120 --> 00:10:40,800 DIFFERENTIATE BETWEEN FDG AND 248 00:10:40,800 --> 00:10:44,920 GLUCOSE, YOU END UP WITH THIS 249 00:10:44,920 --> 00:10:48,280 MOLECULE, GOES INSIDE THE CELL, 250 00:10:48,280 --> 00:10:48,960 PHOSPHORYLATED, BECOMES CHARGED, 251 00:10:48,960 --> 00:10:51,040 DOES NOT LEAVE THE CELL, YOU END 252 00:10:51,040 --> 00:10:59,960 UP WITH A MAP OF GLUCOSE 253 00:10:59,960 --> 00:11:00,240 METABOLISM. 254 00:11:00,240 --> 00:11:02,480 THAT'S THE BASIS FOR USING IT IN 255 00:11:02,480 --> 00:11:04,120 CANCER IMAGING WHERE IT'S MADE A 256 00:11:04,120 --> 00:11:05,240 HUGE IMPACT ON DIAGNOSIS AND 257 00:11:05,240 --> 00:11:06,080 MANAGEMENT OF PATIENTS. 258 00:11:06,080 --> 00:11:09,440 BUT IT'S NOT ONLY IN CANCER THAT 259 00:11:09,440 --> 00:11:09,800 IT'S IMPORTANT. 260 00:11:09,800 --> 00:11:13,000 IT'S ALSO IMPORTANT IN INFECTION 261 00:11:13,000 --> 00:11:16,360 AND INFLAMMATION BECAUSE WE KNOW 262 00:11:16,360 --> 00:11:19,520 ACTIVATED IMMUNE CELLS 263 00:11:19,520 --> 00:11:22,480 UPREGULATE TO GLUT-1 LEVELS, 264 00:11:22,480 --> 00:11:25,240 BECOMING MORE AND MORE FDG-AVID, 265 00:11:25,240 --> 00:11:30,280 THIS IS A STUDY AT NIAID, HER 266 00:11:30,280 --> 00:11:35,000 PATIENTS, SOME DEVELOPED WHAT WE 267 00:11:35,000 --> 00:11:38,040 REFER TO AS IRIS, AND WHERE YOU 268 00:11:38,040 --> 00:11:40,840 GET ACTIVATION OF IMMUNE CELLS 269 00:11:40,840 --> 00:11:42,280 AS A RESULT OF TREATING 270 00:11:42,280 --> 00:11:42,640 PATIENTS. 271 00:11:42,640 --> 00:11:46,600 YOU CAN SEE HERE THAT AFTER 272 00:11:46,600 --> 00:11:47,560 TREATMENT, GLUT-1 EXPRESSION 273 00:11:47,560 --> 00:11:51,480 INCREASED IN THESE MONOCYTES, 274 00:11:51,480 --> 00:11:55,840 THE BASIS FOR IMAGING INFECTION 275 00:11:55,840 --> 00:11:58,240 INFLAMMATION IN THOSE PATIENTS. 276 00:11:58,240 --> 00:11:59,080 WHICH BRINGS US TO THE BRAIN, 277 00:11:59,080 --> 00:12:01,520 WHERE THINGS ARE A LITTLE BIT 278 00:12:01,520 --> 00:12:03,240 MORE COMPLICATED, BECAUSE IN THE 279 00:12:03,240 --> 00:12:04,680 BRAIN, IT'S NOT ONLY THESE 280 00:12:04,680 --> 00:12:06,320 IMMUNE CELLS THAT WE'RE TALKING 281 00:12:06,320 --> 00:12:11,240 ABOUT, BUT WE ALSO HAVE NEURONS. 282 00:12:11,240 --> 00:12:14,320 NEURONS ONLY USE GLUCOSE FOR 283 00:12:14,320 --> 00:12:17,480 THEIR ENERGY SUPPLIES, SO 284 00:12:17,480 --> 00:12:20,120 GLUCOSE -- NEURONS TAKE A LOT OF 285 00:12:20,120 --> 00:12:20,720 FDG. 286 00:12:20,720 --> 00:12:22,120 EVERYBODY ASSUMES ALL THE FDG 287 00:12:22,120 --> 00:12:25,120 UPTAKE OR MOST IN THE BRAIN IS 288 00:12:25,120 --> 00:12:28,960 ACTUALLY IN NEURONS, BUT 289 00:12:28,960 --> 00:12:30,600 NOWADAYS THERE ARE QUESTIONS 290 00:12:30,600 --> 00:12:33,640 ABOUT THE FACT THAT GLIAL CELLS 291 00:12:33,640 --> 00:12:34,880 AND INCLUDING MICROGLIA AND 292 00:12:34,880 --> 00:12:38,120 ASTROCYTES, THAT THEY ARE 293 00:12:38,120 --> 00:12:43,480 ACTUALLY MORE AND MORE 294 00:12:43,480 --> 00:12:45,840 RESPONSIBLE FOR FDG UPTAKE, IN 295 00:12:45,840 --> 00:12:47,560 THE BIOESSENCE STATE, IN ALL 296 00:12:47,560 --> 00:12:49,960 CASES WHAT WE'RE REALLY LOOKING 297 00:12:49,960 --> 00:12:51,680 AT ESSENTIALLY IS TWO EVENTS. 298 00:12:51,680 --> 00:12:55,400 THE FIRST ONE IS IF YOU HAVE 299 00:12:55,400 --> 00:12:56,720 INFLAMMATION, ACTIVATION OF 300 00:12:56,720 --> 00:13:00,200 IMMUNE CELLS, THERE'S INCREASED 301 00:13:00,200 --> 00:13:02,280 GLUT-1, INCREASED USE OF 302 00:13:02,280 --> 00:13:04,560 GLUCOSE, INCREASED FDG UPTAKE. 303 00:13:04,560 --> 00:13:07,040 IF YOU'RE LOSING NEURONS LIKE 304 00:13:07,040 --> 00:13:07,920 HAPPENS WITH ALZHEIMER'S, FOR 305 00:13:07,920 --> 00:13:11,320 EXAMPLE, THEN YOU HAVE DECREASED 306 00:13:11,320 --> 00:13:12,760 FDG UPTAKE. 307 00:13:12,760 --> 00:13:14,360 BEING ABLE TO DECIPHER WHAT'S 308 00:13:14,360 --> 00:13:15,640 HAPPENING IS NOT ALWAYS EASY BUT 309 00:13:15,640 --> 00:13:19,320 CAN YOU DONE IF YOU DESIGN YOUR 310 00:13:19,320 --> 00:13:20,160 STUDIES APPROPRIATELY. 311 00:13:20,160 --> 00:13:22,600 AND IF YOU DO LONGITUDINAL 312 00:13:22,600 --> 00:13:23,880 IMAGING, FOR EXAMPLE. 313 00:13:23,880 --> 00:13:26,560 IN THE CLINIC, THIS INCREASED 314 00:13:26,560 --> 00:13:30,120 FDG UPTAKE ASSOCIATED WITH 315 00:13:30,120 --> 00:13:32,000 INFLAMMATION IS WHAT WE USE TO 316 00:13:32,000 --> 00:13:33,960 ANSWER QUESTIONS. 317 00:13:33,960 --> 00:13:35,640 ONE COMMON QUESTION IN HIV 318 00:13:35,640 --> 00:13:38,440 POSITIVE PATIENTS, FOR EXAMPLE, 319 00:13:38,440 --> 00:13:40,120 IS DIFFERENTIATING THE ETIOLOGY 320 00:13:40,120 --> 00:13:41,640 OF ENHANCING LESIONS OF THE 321 00:13:41,640 --> 00:13:46,240 BRAIN, SO PATIENTS WITH HIV 322 00:13:46,240 --> 00:13:53,120 PRESENT, THE QUESTION IS, IS 323 00:13:53,120 --> 00:13:53,520 THIS TUBERCULOSIS? 324 00:13:53,520 --> 00:13:56,720 THERE'S A LOT OF LITERATURE 325 00:13:56,720 --> 00:14:03,680 ABOUT USING FDG UPTAKE VALUES, 326 00:14:03,680 --> 00:14:04,240 SPECIFICALLY SUV-MAX. 327 00:14:04,240 --> 00:14:07,040 AND IF YOU FIND THE SUV-MAX 328 00:14:07,040 --> 00:14:08,720 VALUES ARE THE LOW RANGE, YOU 329 00:14:08,720 --> 00:14:12,760 THINK MORE ALONG THE LINES OF 330 00:14:12,760 --> 00:14:15,240 TOXOPLASMOSIS, IN THE HIGH RANGE 331 00:14:15,240 --> 00:14:16,360 LYMPHOMA, AND TUBERCULOSIS FALLS 332 00:14:16,360 --> 00:14:17,120 IN BETWEEN. 333 00:14:17,120 --> 00:14:19,200 IT'S VERY IMPORTANT TO KNOW 334 00:14:19,200 --> 00:14:22,680 THESE ARE JUST GUIDELINES, 335 00:14:22,680 --> 00:14:25,440 SUV-MAX VALUES VARY DEPENDING ON 336 00:14:25,440 --> 00:14:26,760 THE SCANNER YOU'RE USING, 337 00:14:26,760 --> 00:14:27,480 RECONSTRUCTION METHOD, ET 338 00:14:27,480 --> 00:14:37,640 CETERA. 339 00:14:37,640 --> 00:14:38,760 SO THESE ARE GUIDELINES. 340 00:14:38,760 --> 00:14:40,960 OFTEN WE CAN GIVE AN ANSWER OF 341 00:14:40,960 --> 00:14:42,400 THE MOST LIKELY POSSIBILITY OF 342 00:14:42,400 --> 00:14:43,200 WHAT THE LESION IS. 343 00:14:43,200 --> 00:14:45,200 AN IMPORTANT THING IN THE CLINIC 344 00:14:45,200 --> 00:14:49,480 THOUGH IS TO KNOW THAT 345 00:14:49,480 --> 00:14:50,400 IMMUNOCOMPROMISED PATIENTS WHO 346 00:14:50,400 --> 00:14:52,040 DON'T MOUNT STRONG IMMUNE 347 00:14:52,040 --> 00:14:53,160 REACTION UPTAKE WITH FDG IS 348 00:14:53,160 --> 00:14:53,440 LOWER. 349 00:14:53,440 --> 00:15:04,560 FOR EXAMPLE, THIS IS A VERY UGLY 350 00:15:04,560 --> 00:15:07,400 LOOKING ASPERGILLOMA, IT CAN BE 351 00:15:07,400 --> 00:15:08,440 VERY HELPFUL, DIFFERENTIATING 352 00:15:08,440 --> 00:15:10,560 FROM TUMOR, FOR EXAMPLE. 353 00:15:10,560 --> 00:15:18,080 THIS IS A VERY INTERESTING CASE, 354 00:15:18,080 --> 00:15:20,920 A PATIENT WITH CNS LYMPHOMA, 355 00:15:20,920 --> 00:15:23,440 AFTER TREATMENT THE PATIENT 356 00:15:23,440 --> 00:15:27,280 COMES BACK WITH A HYPER 357 00:15:27,280 --> 00:15:28,040 METABOLIC COMPONENT, WHICH TURNS 358 00:15:28,040 --> 00:15:29,640 OUT TO BE THE CANCER. 359 00:15:29,640 --> 00:15:32,680 THEN YOU HAVE A LESS METABOLIC 360 00:15:32,680 --> 00:15:36,680 COMPONENT, THAT TURNED OUT TO BE 361 00:15:36,680 --> 00:15:37,640 AN ASPERGILLOMA. 362 00:15:37,640 --> 00:15:38,840 THIS DIFFERENTIAL UPTAKE BETWEEN 363 00:15:38,840 --> 00:15:40,920 INFECTION AND TUMOR CAN BE 364 00:15:40,920 --> 00:15:41,560 HELPFUL IN DIAGNOSING WHAT'S 365 00:15:41,560 --> 00:15:46,720 HAPPENING IN THE BRAIN OF THOSE 366 00:15:46,720 --> 00:15:47,000 PATIENTS. 367 00:15:47,000 --> 00:15:48,480 THE OTHER USE OF FDG PET THAT WE 368 00:15:48,480 --> 00:15:53,520 HAVE HERE AT NIH IS IN 369 00:15:53,520 --> 00:15:56,600 COLLABORATION WITH DOCTORS 370 00:15:56,600 --> 00:15:57,720 LEONAKIS AND WILLIAMSON, 371 00:15:57,720 --> 00:15:58,880 PATIENTS WITH FUNGAL INFECTIONS. 372 00:15:58,880 --> 00:16:00,480 THE PROBLEM IS THAT EVEN WHEN 373 00:16:00,480 --> 00:16:01,560 YOU TREAT THEM, YOU ALMOST 374 00:16:01,560 --> 00:16:04,520 ALWAYS END UP WITH A CERTAIN 375 00:16:04,520 --> 00:16:06,680 AMOUNT OF ENHANCEMENT ON MRI, 376 00:16:06,680 --> 00:16:09,440 AND THE QUESTION IS IS THERE 377 00:16:09,440 --> 00:16:10,200 STILL AN INFECTIOUS PROCESS 378 00:16:10,200 --> 00:16:11,080 GOING ON? 379 00:16:11,080 --> 00:16:13,680 WE'VE BEEN USING PET IMAGING TO 380 00:16:13,680 --> 00:16:16,240 FOLLOW THOSE PATIENTS AND SEE IF 381 00:16:16,240 --> 00:16:19,040 WE CAN DETECT A DECREASE IN FDG 382 00:16:19,040 --> 00:16:20,240 PET UPTAKE THAT INDICATES 383 00:16:20,240 --> 00:16:21,440 RESPONSE TO TREATMENT. 384 00:16:21,440 --> 00:16:25,680 IT DOESN'T MEAN THAT THE FUNGUS 385 00:16:25,680 --> 00:16:26,800 IS GONE, ONLY THEY ARE 386 00:16:26,800 --> 00:16:27,360 RESPONDING TO TREATMENT. 387 00:16:27,360 --> 00:16:29,760 AS LONG AS YOU CAN CONTROL THEM 388 00:16:29,760 --> 00:16:30,960 WITHOUT THIS FDG UPTAKE COMING 389 00:16:30,960 --> 00:16:35,320 BACK, THEN YOU'RE IN GOOD SHAPE. 390 00:16:35,320 --> 00:16:43,240 THIS IS ANOTHER EXAMPLE OF CNS, 391 00:16:43,240 --> 00:16:45,200 A PATIENT WITH ENHANCEMENT, 392 00:16:45,200 --> 00:16:49,040 THICKENING IN THE DISTAL CORD, 393 00:16:49,040 --> 00:16:51,960 ON FDG PET WE SAW EXTENSIVE 394 00:16:51,960 --> 00:16:54,160 AMOUNT OF FDG UPTAKE CONSISTENT 395 00:16:54,160 --> 00:16:56,560 WITH INFLAMMATORY PROCESS THAT'S 396 00:16:56,560 --> 00:16:59,080 HAPPENING. 397 00:16:59,080 --> 00:17:00,680 ON FOLLOW-UP HOWEVER THE FDG 398 00:17:00,680 --> 00:17:02,080 UPTAKE AFTER TREATMENT GOES DOWN 399 00:17:02,080 --> 00:17:04,280 QUITE A BIT, FASTER THAN THE 400 00:17:04,280 --> 00:17:08,160 CHANGES WE'RE SEEING ON MRI. 401 00:17:08,160 --> 00:17:12,480 WHEN RESOLVED STILL HAVE 402 00:17:12,480 --> 00:17:14,240 ENHANCEMENT ON MRI. 403 00:17:14,240 --> 00:17:18,240 FDG BECOMES COMPLEMENTARY TO 404 00:17:18,240 --> 00:17:19,360 CONVENTIONAL IMAGING. 405 00:17:19,360 --> 00:17:22,320 AND A CLINICAL EXAMPLE I'M GOING 406 00:17:22,320 --> 00:17:24,400 TO SHOW, AGAIN POINTING OUT TO 407 00:17:24,400 --> 00:17:27,240 THE FACT FDG MIGHT NOT DETECT 408 00:17:27,240 --> 00:17:28,840 WHEN THE IMMUNE SYSTEM IS NOT 409 00:17:28,840 --> 00:17:32,400 WELL BUT IF YOU HAVE IMMUNE 410 00:17:32,400 --> 00:17:34,320 RECOVERY, LIKE IN IRIS PATIENTS, 411 00:17:34,320 --> 00:17:35,880 YOU MIGHT BE ABLE TO DETECT 412 00:17:35,880 --> 00:17:37,720 CHANGES EASILY. 413 00:17:37,720 --> 00:17:44,640 THIS IS A PATIENT WITH PML IRIS, 414 00:17:44,640 --> 00:17:49,560 DR. SERETI'S PATIENT, HE 415 00:17:49,560 --> 00:17:51,760 PRESENTED WITH ABNORMAL 416 00:17:51,760 --> 00:17:54,640 ENHANCEMENT AFTER TREATMENT, 417 00:17:54,640 --> 00:17:55,640 INCREASED FDG UPTAKE, PROBABLY 418 00:17:55,640 --> 00:17:59,440 ON THE CD 8 POSITIVE T CELLS 419 00:17:59,440 --> 00:18:01,640 THAT HAVE CONTRIBUTED TO THIS 420 00:18:01,640 --> 00:18:04,480 IMMUNE RECOVERY, AND FDG UPTAKE. 421 00:18:04,480 --> 00:18:06,920 EVENTUALLY THIS UPTAKE GOES AWAY 422 00:18:06,920 --> 00:18:10,040 SUGGESTING OR CONSISTENT WITH 423 00:18:10,040 --> 00:18:10,960 RESPONSE TO TREATMENT. 424 00:18:10,960 --> 00:18:12,680 BUT AS I SAID EARLIER IT'S NOT 425 00:18:12,680 --> 00:18:14,560 ONLY IN THE CLINIC THAT PET 426 00:18:14,560 --> 00:18:18,400 IMAGING AND FDG PET IS VERY 427 00:18:18,400 --> 00:18:19,520 IMPORTANT. 428 00:18:19,520 --> 00:18:21,640 IN FACT, IN THE RESEARCH THESE 429 00:18:21,640 --> 00:18:23,760 MODALITIES CAN BE VERY IMPORTANT 430 00:18:23,760 --> 00:18:25,720 TO BETTER UNDERSTAND WHAT'S 431 00:18:25,720 --> 00:18:29,000 HAPPENING IN CNS INFECTIONS 432 00:18:29,000 --> 00:18:31,200 BECAUSE OFTEN THE CNS INFECTIONS 433 00:18:31,200 --> 00:18:37,960 CAN HAVE POORLY UNDERSTAND PAT 434 00:18:37,960 --> 00:18:39,600 -- PATHOPHYSIOLOGY, WE CAN 435 00:18:39,600 --> 00:18:40,600 UNDERSTAND WHAT'S HAPPENING, 436 00:18:40,600 --> 00:18:41,680 MITIGATING OR CONTRIBUTING 437 00:18:41,680 --> 00:18:43,520 FACTORS TO DAMAGE IN THE BRAIN. 438 00:18:43,520 --> 00:18:47,560 YOU CAN USE THEM TO ASSESS THE 439 00:18:47,560 --> 00:18:50,000 LONG TERM SEQUELAE OF CNS 440 00:18:50,000 --> 00:18:50,840 INFECTIONS, EVALUATE EFFICACY OF 441 00:18:50,840 --> 00:18:51,200 TREATMENT. 442 00:18:51,200 --> 00:18:53,840 I'M GOING TO GIVE EXAMPLES OF 443 00:18:53,840 --> 00:18:56,640 ALL OF THESE. 444 00:18:56,640 --> 00:19:00,240 A HAVE GOOD EXAMPLE IS NEUROHIV, 445 00:19:00,240 --> 00:19:00,840 MULTI-FACTORIAL, HIV POSITIVE 446 00:19:00,840 --> 00:19:03,240 PATIENTS IN THE EARLY DAYS OF 447 00:19:03,240 --> 00:19:04,920 THE EPIDEMIC USED TO HAVE SEVERE 448 00:19:04,920 --> 00:19:08,760 DISEASE AND END UP IN DEMENTIA. 449 00:19:08,760 --> 00:19:12,040 MORE RECENTLY THOUGH AFTER MAJOR 450 00:19:12,040 --> 00:19:14,840 ADVANCES IN THERAPY, PATIENTS 451 00:19:14,840 --> 00:19:16,840 ARE SURVIVING MUCH LONGER, 452 00:19:16,840 --> 00:19:18,120 NEUROCOGNITIVE FUNCTION NOT AS 453 00:19:18,120 --> 00:19:19,040 SIGNIFICANT BUT STILL EXISTS, 454 00:19:19,040 --> 00:19:20,840 IT'S A REAL PROBLEM AND AFFECTS 455 00:19:20,840 --> 00:19:22,280 THE QUALITY OF LIFE. 456 00:19:22,280 --> 00:19:23,240 THE QUESTION IS, WHAT IS 457 00:19:23,240 --> 00:19:26,680 HAPPENING IN THE BRAIN OF THOSE 458 00:19:26,680 --> 00:19:30,960 PATIENTS, SO THEY ARE OPTIMALLY 459 00:19:30,960 --> 00:19:31,200 TREATED. 460 00:19:31,200 --> 00:19:33,120 THE ASSUMPTION OF OF 461 00:19:33,120 --> 00:19:34,240 NEUROINFLAMMATION WITH 462 00:19:34,240 --> 00:19:36,720 PRODUCTION OF CHEMOKINES, 463 00:19:36,720 --> 00:19:45,600 VARIETY OF OTHER COMPOUNDS, WE 464 00:19:45,600 --> 00:19:51,040 KNOW GP 120 ARE NEUROTOXIC, 465 00:19:51,040 --> 00:19:52,800 ASTROCYTIC LOST, INCREASED 466 00:19:52,800 --> 00:19:55,640 PRODUCTION COULD BE 467 00:19:55,640 --> 00:19:56,600 CONTRIBUTING, EFFECT OF 468 00:19:56,600 --> 00:19:57,240 ANTIRETROVIRAL THERAPY, 469 00:19:57,240 --> 00:20:01,840 SOMETHING NOW WE'RE THINKING 470 00:20:01,840 --> 00:20:02,640 MORE ABOUT, THAT'S COMORBIDITIES 471 00:20:02,640 --> 00:20:03,920 OF CARDIOVASCULAR DISEASE. 472 00:20:03,920 --> 00:20:06,040 WITH USE OF MOLECULAR IMAGING 473 00:20:06,040 --> 00:20:11,040 AND THE ABILITY TO ACTUALLY 474 00:20:11,040 --> 00:20:12,400 SELECT TECHNOLOGIES ONE CAN 475 00:20:12,400 --> 00:20:15,720 PARSE OUT CONTRIBUTION OF THESE 476 00:20:15,720 --> 00:20:18,480 DIFFERENT FACTORS, AND TO THE 477 00:20:18,480 --> 00:20:23,280 END RESULT OF NEURONAL INJURY, 478 00:20:23,280 --> 00:20:23,800 AND HOPEFULLY PROPOSE 479 00:20:23,800 --> 00:20:27,120 IMPROVEMENT TO THE WAY WE'RE 480 00:20:27,120 --> 00:20:29,760 MANAGING THOSE PATIENTS. 481 00:20:29,760 --> 00:20:34,120 NEURO-HIV THERE ARE MULTIPLE 482 00:20:34,120 --> 00:20:36,160 TARGETS, PERHAPS THE EASIEST IS 483 00:20:36,160 --> 00:20:37,320 GLUCOSE METABOLISM WHICH AS I 484 00:20:37,320 --> 00:20:39,480 SAID EARLIER IS USUALLY A 485 00:20:39,480 --> 00:20:41,840 COMBINATION OF NEUROINFLAMMATION 486 00:20:41,840 --> 00:20:46,720 AS WELL AS NEURONAL FUNCTION OR 487 00:20:46,720 --> 00:20:47,040 DYSFUNCTION. 488 00:20:47,040 --> 00:20:50,120 WE USED FDG PET TO EVALUATE 489 00:20:50,120 --> 00:20:54,600 PATIENTS A.R.T. NAIVE, ADVANCED 490 00:20:54,600 --> 00:20:57,240 HIV INFECTION WITH VERY LOW CD 4 491 00:20:57,240 --> 00:20:59,400 COUNTS, IMAGE THEM WITH FDG AT 492 00:20:59,400 --> 00:20:59,640 BASELINE. 493 00:20:59,640 --> 00:21:01,440 THEN WE IMAGE THEM AFTER THEY 494 00:21:01,440 --> 00:21:02,760 WERE TREATED. 495 00:21:02,760 --> 00:21:04,440 WITHIN WEEKS FROM THEIR 496 00:21:04,440 --> 00:21:05,440 TREATMENT. 497 00:21:05,440 --> 00:21:07,160 AND IN ALL HONESTY WE DIDN'T 498 00:21:07,160 --> 00:21:10,640 EXPECT TO SEE A LOT OF CHANGE IN 499 00:21:10,640 --> 00:21:12,200 A FEW WEEKS. 500 00:21:12,200 --> 00:21:15,440 BUT WE FOUND SIGNIFICANT DROP IN 501 00:21:15,440 --> 00:21:22,120 FDG UPTAKE AND THE BASAL 502 00:21:22,120 --> 00:21:24,080 GANGLIA, CAUDATE, HYPOTHALAMUS, 503 00:21:24,080 --> 00:21:26,920 WHICH CORRELATED POSITIVELY WITH 504 00:21:26,920 --> 00:21:31,200 A DROP IN INTERLEUKIN 6 OR SCD 505 00:21:31,200 --> 00:21:31,680 14 INFLAMMATORY MARKERS 506 00:21:31,680 --> 00:21:33,640 SUGGESTING THERE HAS BEEN OR WAS 507 00:21:33,640 --> 00:21:34,920 INFLAMMATORY PROCESS HAPPENING 508 00:21:34,920 --> 00:21:36,160 AT THIS LEVEL WHICH AFTER 509 00:21:36,160 --> 00:21:40,280 CONTROL OF THE VIRAL INFECTION, 510 00:21:40,280 --> 00:21:42,120 AFTER CONTROL OF THE 511 00:21:42,120 --> 00:21:44,120 INFLAMMATION, THE AMOUNT OF 512 00:21:44,120 --> 00:21:45,440 UPTAKE DECREASED. 513 00:21:45,440 --> 00:21:47,480 WE SAW THE CORTEX STARTED 514 00:21:47,480 --> 00:21:49,600 ACTUALLY SHOWING MORE FDG 515 00:21:49,600 --> 00:21:51,240 UPTAKE, SPECIFICALLY IN THE 516 00:21:51,240 --> 00:21:53,640 FRONTAL LOBE, WHERE THE CHANGES 517 00:21:53,640 --> 00:21:57,240 WERE STATISTICALLY SIGNIFICANT. 518 00:21:57,240 --> 00:21:59,920 AND, AGAIN, THAT CORRELATED 519 00:21:59,920 --> 00:22:01,560 POSITIVELY ACTUALLY CORRELATED 520 00:22:01,560 --> 00:22:04,040 NEGATIVELY WITH IMPROVEMENT OF 521 00:22:04,040 --> 00:22:04,600 NEUROINFLAMMATION. 522 00:22:04,600 --> 00:22:06,800 SO THERE SEEMS TO BE A 523 00:22:06,800 --> 00:22:13,240 REVERSIBLE CORTICAL DYSFUNCTION 524 00:22:13,240 --> 00:22:17,080 OCCURRING IN THE STAGE, ONCE YOU 525 00:22:17,080 --> 00:22:18,000 DECREASE INFLAMMATION, DECREASE 526 00:22:18,000 --> 00:22:20,240 VIRAL REPLICATION YOU HAVE 527 00:22:20,240 --> 00:22:21,440 RECOVERY OF SOME FUNCTION 528 00:22:21,440 --> 00:22:22,320 SUGGESTING IT'S IMPORTANT TO 529 00:22:22,320 --> 00:22:25,400 START TREATMENT VERY EARLY ON. 530 00:22:25,400 --> 00:22:27,360 SUBSET OF THOSE PATIENTS CAME 531 00:22:27,360 --> 00:22:29,880 BACK TWO YEARS LATER, AT THAT 532 00:22:29,880 --> 00:22:32,600 POINT WE FOUND THAT THE UPTAKE, 533 00:22:32,600 --> 00:22:34,800 FDG UPTAKE IN THE BASAL GANGLIA 534 00:22:34,800 --> 00:22:35,800 WAS EVEN LOWER. 535 00:22:35,800 --> 00:22:38,040 AND WHEN WE COMPARED THEM TO 536 00:22:38,040 --> 00:22:39,720 NORMAL CONTROLS, THE UPTAKE WAS 537 00:22:39,720 --> 00:22:41,800 ACTUALLY LOWER THAN NORMAL 538 00:22:41,800 --> 00:22:42,040 CONTROLS. 539 00:22:42,040 --> 00:22:43,240 SO THAT ABNORMALLY LOW. 540 00:22:43,240 --> 00:22:45,000 AND AT THIS POINT THE ONLY 541 00:22:45,000 --> 00:22:46,480 CONCLUSION IS THAT THERE HAS 542 00:22:46,480 --> 00:22:49,120 BEEN NEURONAL LOSS HAPPENING IN 543 00:22:49,120 --> 00:22:50,640 THE BASAL GANGLIA, AND THAT'S 544 00:22:50,640 --> 00:22:51,440 NOT UNUSUAL CONSIDERING THESE 545 00:22:51,440 --> 00:22:56,240 ARE THE AREAS THAT WE'RE MOST 546 00:22:56,240 --> 00:22:57,200 NEURAL INFLAMMATION. 547 00:22:57,200 --> 00:22:58,520 THAT, AGAIN, TAKES US BACK TO 548 00:22:58,520 --> 00:23:01,840 WHAT WE REFER TO AS THE LEGACY 549 00:23:01,840 --> 00:23:04,280 FACT, A CERTAIN AMOUNT OF 550 00:23:04,280 --> 00:23:05,480 NEUROCOGNITIVE DYSFUNCTION OR 551 00:23:05,480 --> 00:23:07,320 NEURONAL LOSS THAT HAPPENS IN 552 00:23:07,320 --> 00:23:11,480 EARLY STAGE OF HIV INFECTION 553 00:23:11,480 --> 00:23:12,440 ASSOCIATED WITH RESIDUAL 554 00:23:12,440 --> 00:23:13,240 NEUROCOGNITIVE DEFICIT THAT'S 555 00:23:13,240 --> 00:23:22,000 NOT GOING TO IMPROVE WITH 556 00:23:22,000 --> 00:23:23,640 ANTIRETROVIRAL TREATMENT, SO 557 00:23:23,640 --> 00:23:25,120 EARLIER TREATMENT CAN BETTER SO 558 00:23:25,120 --> 00:23:27,360 DAMAGE CAN BE ALLEVIATED. 559 00:23:27,360 --> 00:23:29,320 WE LOOKED AT PATIENTS, FROM THE 560 00:23:29,320 --> 00:23:30,520 ALL HANDS PROTOCOL. 561 00:23:30,520 --> 00:23:31,840 THEY HAD BEEN INFECTED FOR MUCH 562 00:23:31,840 --> 00:23:35,040 LONGER PERIODS OF TIME AND 563 00:23:35,040 --> 00:23:36,680 TREATED, APPROXIMATELY 20 YEARS. 564 00:23:36,680 --> 00:23:39,960 WE WANTED TO SEE WHAT HAPPENS 565 00:23:39,960 --> 00:23:40,720 WAY BEYOND TWO YEARS OF 566 00:23:40,720 --> 00:23:41,840 FOLLOW-UP WE HAD. 567 00:23:41,840 --> 00:23:43,600 IN THIS GROUP OF PATIENTS, THERE 568 00:23:43,600 --> 00:23:46,640 WERE TWO MAJOR FINDINGS. 569 00:23:46,640 --> 00:23:52,240 FIRST, WE NOTICED , WE COMPARED 570 00:23:52,240 --> 00:23:54,840 TO HEALTHY CONTROLS AND CONTROLS 571 00:23:54,840 --> 00:23:57,040 WITH COMORBIDITIES AND FOUND 572 00:23:57,040 --> 00:24:00,480 THAT DOING A VARIABLE SELECTION 573 00:24:00,480 --> 00:24:01,960 MODEL, METABOLISM WAS PREDICTED 574 00:24:01,960 --> 00:24:04,640 BY HIV STATUS SUGGESTING DIRECT 575 00:24:04,640 --> 00:24:07,680 HIV EFFECT. 576 00:24:07,680 --> 00:24:08,640 PERSISTENT OR RESIDUAL DESPITE 577 00:24:08,640 --> 00:24:11,400 THE FACT THOSE PATIENTS ARE 578 00:24:11,400 --> 00:24:12,400 OPTIMALLY TREATED. 579 00:24:12,400 --> 00:24:13,920 WHAT WAS EVEN MORE INTERESTING 580 00:24:13,920 --> 00:24:16,760 IS THAT WHEN WE LOOKED AT THE 581 00:24:16,760 --> 00:24:17,760 WHOLE BRAIN METABOLISM, IT 582 00:24:17,760 --> 00:24:20,240 WASN'T HIV THAT WAS THE CULPRIT 583 00:24:20,240 --> 00:24:20,600 ANYMORE. 584 00:24:20,600 --> 00:24:23,440 IN FACT, IN THOSE PATIENTS, IT 585 00:24:23,440 --> 00:24:28,600 WAS CARDIOVASCULAR DISEASE THAT 586 00:24:28,600 --> 00:24:31,000 WAS ASSOCIATED WITH THE WORST 587 00:24:31,000 --> 00:24:33,080 HYPO METABOLISM, AND WHEN WE DID 588 00:24:33,080 --> 00:24:40,280 THE STATISTICAL ANALYSIS, THE 589 00:24:40,280 --> 00:24:41,840 WHOLE BRAIN METABOLISM PREDICTED 590 00:24:41,840 --> 00:24:42,880 BY CARDIOVASCULAR DISEASE, NOT 591 00:24:42,880 --> 00:24:44,320 HIV STATUS. 592 00:24:44,320 --> 00:24:46,200 IT'S IMPORTANT AS PHYSICIANS 593 00:24:46,200 --> 00:24:47,000 TAKING CARE OF HIV-POSITIVE 594 00:24:47,000 --> 00:24:47,920 PATIENTS IT'S IMPORTANT TO KNOW 595 00:24:47,920 --> 00:24:49,800 IT'S NOT ENOUGH TO TREAT THE 596 00:24:49,800 --> 00:24:50,120 INFECTION. 597 00:24:50,120 --> 00:24:54,800 ONE HAS TO BE VERY AGGRESSIVE, 598 00:24:54,800 --> 00:24:55,400 TARGETING CARDIOVASCULAR 599 00:24:55,400 --> 00:24:58,520 DISEASE, IF YOU WANT TO STOP 600 00:24:58,520 --> 00:25:02,320 NEUROCOGNITIVE DYSFUNCTION FROM 601 00:25:02,320 --> 00:25:03,600 HAPPENING OR WORSENING. 602 00:25:03,600 --> 00:25:07,240 THERE ARE ALSO OTHER WAYS OF 603 00:25:07,240 --> 00:25:08,560 LOOKING AT THE BRAIN, 604 00:25:08,560 --> 00:25:09,520 NEUROINFLAMMATION IN THE BRAIN. 605 00:25:09,520 --> 00:25:11,480 IN FACT A MORE SPECIFIC WAY OF 606 00:25:11,480 --> 00:25:14,840 LOOKING AT THAT, THAT IS 607 00:25:14,840 --> 00:25:16,440 TARGETING MARKERS THAT ARE 608 00:25:16,440 --> 00:25:18,240 EXPRESSED IN IMMUNE CELLS AND 609 00:25:18,240 --> 00:25:20,120 ACTIVATED IN IMMUNE CELLS. 610 00:25:20,120 --> 00:25:21,560 PERHAPS THE MOST FAMOUS TARGET 611 00:25:21,560 --> 00:25:25,960 IS WHAT WE REFER TO AS 612 00:25:25,960 --> 00:25:31,000 TRANSLOCATOR PROTEIN, A MEMBRANE 613 00:25:31,000 --> 00:25:32,520 RECEPTOR, THAT IS EXPRESSED IN A 614 00:25:32,520 --> 00:25:34,600 LOT OF IMMUNE CELLS BUT IN THE 615 00:25:34,600 --> 00:25:36,800 BRAIN IT'S EXPRESSED IN 616 00:25:36,800 --> 00:25:43,560 MICROGLIA, AND IN MONOCYTE 617 00:25:43,560 --> 00:25:44,640 DERIVED MACROPHAGES AND OTHER 618 00:25:44,640 --> 00:25:45,440 CELL TYPES. 619 00:25:45,440 --> 00:25:51,120 YOU CAN SEE HERE THE STAINING 620 00:25:51,120 --> 00:25:52,480 LOCALIZES WITH MICROGLIAL AND 621 00:25:52,480 --> 00:25:53,280 ASTROCYTIC MARKERS. 622 00:25:53,280 --> 00:25:55,880 THE GOOD THING IS THAT IN NORMAL 623 00:25:55,880 --> 00:25:58,480 BRAIN, THE LEVEL OF EXPRESSION 624 00:25:58,480 --> 00:26:01,440 OF TSPO IS LOVE. 625 00:26:01,440 --> 00:26:02,080 IS LOW. 626 00:26:02,080 --> 00:26:04,160 IF THERE'S ANY KIND OF INJURY 627 00:26:04,160 --> 00:26:06,120 YOU GET UPREGULATED EXPRESSION 628 00:26:06,120 --> 00:26:11,840 OF TSPO, AND THAT'S REFLECTION 629 00:26:11,840 --> 00:26:12,280 OF NEUROINFLAMMATIONS. 630 00:26:12,280 --> 00:26:14,280 IF YOU CAN MEASURE TSPO, YOU CAN 631 00:26:14,280 --> 00:26:15,760 MEASURE INFLAMMATION IN THE 632 00:26:15,760 --> 00:26:16,200 BRAIN. 633 00:26:16,200 --> 00:26:18,440 WE HAD ONE LIGAND FOR THE 634 00:26:18,440 --> 00:26:26,360 LONGEST PERIOD OF TIME, FOR TSPO 635 00:26:26,360 --> 00:26:29,240 IMAGING, BUT THAT HAD 636 00:26:29,240 --> 00:26:31,120 NON-SPECIFIC BINDING, IT DIDN'T 637 00:26:31,120 --> 00:26:33,640 HAVE VERY GOOD BIOAVAILABILITY. 638 00:26:33,640 --> 00:26:35,840 SO PEOPLE STARTED OR A GROUP 639 00:26:35,840 --> 00:26:36,920 STARTED WORKING ON SECOND 640 00:26:36,920 --> 00:26:37,960 GENERATION TSPO LIGANDS. 641 00:26:37,960 --> 00:26:43,280 ONE OF THE FIRST SECOND 642 00:26:43,280 --> 00:26:44,000 GENERATION LIGANDS WAS DEVELOPED 643 00:26:44,000 --> 00:26:48,760 AT NIH BY DR. ENNIS AND DR. 644 00:26:48,760 --> 00:26:51,640 PIKE, AND IT WAS A GREAT LIGAND 645 00:26:51,640 --> 00:26:55,880 AND ACTUALLY LED TO MORE AND 646 00:26:55,880 --> 00:26:56,840 MORE DISCOVERY ABOUT TSPO. 647 00:26:56,840 --> 00:27:00,240 WHICH I'M NOT GOING TO GO INTO 648 00:27:00,240 --> 00:27:01,960 DETAILS OF. 649 00:27:01,960 --> 00:27:04,680 BUT TSPO IS ONE OF THE MOST 650 00:27:04,680 --> 00:27:06,560 AVAILABLE AND BEST TARGETS, SO 651 00:27:06,560 --> 00:27:08,040 WE WANTED TO BETTER UNDERSTAND 652 00:27:08,040 --> 00:27:11,600 WHAT'S HAPPENING IN THE BRAINS 653 00:27:11,600 --> 00:27:12,840 OF HIV-INFECTED PATIENTS IN THE 654 00:27:12,840 --> 00:27:14,520 EARLY STAGES OF DISEASE. 655 00:27:14,520 --> 00:27:15,480 BUT BECAUSE WE CANNOT IMAGE 656 00:27:15,480 --> 00:27:18,040 PATIENTS BEFORE THEY ARE 657 00:27:18,040 --> 00:27:20,960 INFECTED WE DECIDED TO USE AN 658 00:27:20,960 --> 00:27:23,320 ANIMAL MODEL OF INFECTION, AND 659 00:27:23,320 --> 00:27:24,440 THAT IS SIV-INFECTED MONKEY. 660 00:27:24,440 --> 00:27:28,200 THIS WAS A COLLABORATION WITH 661 00:27:28,200 --> 00:27:32,560 DR. VANESSA HIRSCH, DR. DEMASS 662 00:27:32,560 --> 00:27:37,800 YO AND DR. NATH, INFECTED, AND 663 00:27:37,800 --> 00:27:46,120 USE A LIGAND, WE HAD TO GET 664 00:27:46,120 --> 00:27:48,640 CREATIVE WITH BOLUS METHODS, 665 00:27:48,640 --> 00:27:49,840 RECORD ACTIVITY VALUES IN 666 00:27:49,840 --> 00:27:50,800 DIFFERENT LOCATIONS IN THE BRAIN 667 00:27:50,800 --> 00:27:52,760 OVER TIME. 668 00:27:52,760 --> 00:27:55,640 SO WE PERFORMED THIS 669 00:27:55,640 --> 00:27:59,120 EQUILIBRIUM -- THIS METHOD TO 670 00:27:59,120 --> 00:27:59,920 ESTABLISH EQUILIBRIUM AND 671 00:27:59,920 --> 00:28:02,040 DISPLACE, AND THIS WAY YOU CAN 672 00:28:02,040 --> 00:28:04,640 SEPARATE THE SPECIFIC FROM 673 00:28:04,640 --> 00:28:06,440 NON-SPECIFIC BINDING. 674 00:28:06,440 --> 00:28:08,360 SO WE IMAGING ANIMALS AT 675 00:28:08,360 --> 00:28:10,520 BASELINE, AT FOLLOW-UP, WE HAD 676 00:28:10,520 --> 00:28:13,040 EXPECTED TO SEE THAT AFTER THEY 677 00:28:13,040 --> 00:28:15,280 WERE INOCULATED AND THEY HAD A 678 00:28:15,280 --> 00:28:17,320 LOT OF CSF VIRAL LOAD IN THE 679 00:28:17,320 --> 00:28:20,920 BRAIN AND CSF EXPECTED TO SEE A 680 00:28:20,920 --> 00:28:21,840 LOT OF NEUROINFLAMMATION. 681 00:28:21,840 --> 00:28:27,600 INSTEAD WE SAW A DROP, THIS IS 682 00:28:27,600 --> 00:28:29,800 POST INOCULATION, ACTUALLY THE 683 00:28:29,800 --> 00:28:31,720 TOTAL UPTAKE OR TOTAL 684 00:28:31,720 --> 00:28:33,240 DISTRIBUTION VOLUME IS ACTUALLY 685 00:28:33,240 --> 00:28:34,240 LOWER. 686 00:28:34,240 --> 00:28:35,080 SO INSTEAD OF NEUROINFLAMMATION 687 00:28:35,080 --> 00:28:39,920 WHAT WE WERE SEEING WAS ACTUALLY 688 00:28:39,920 --> 00:28:42,800 MICROGLIAL LOSS AND NO 689 00:28:42,800 --> 00:28:44,000 MICROGLIAL ACTIVATION. 690 00:28:44,000 --> 00:28:45,640 THEN WE TREATED ANIMALS AND SAW 691 00:28:45,640 --> 00:28:47,440 AS WE TREATED ANIMALS AND VIRAL 692 00:28:47,440 --> 00:28:49,320 LOAD GOES DOWN, THIS BINDING 693 00:28:49,320 --> 00:28:50,320 STARTED GOING UP. 694 00:28:50,320 --> 00:28:52,520 AND THEN THE SAME THING HAPPENS 695 00:28:52,520 --> 00:28:54,800 AFTER WE STOPPED TREATMENT. 696 00:28:54,800 --> 00:29:00,320 AGAIN, HAPPENING, THIS ANIMAL, 697 00:29:00,320 --> 00:29:07,640 WE DROPPED THE VIRAL LOAD HAVE 698 00:29:07,640 --> 00:29:09,720 INFLAMMATION, INCREASE, IT GOES 699 00:29:09,720 --> 00:29:10,040 DOWN. 700 00:29:10,040 --> 00:29:11,920 THE ANIMAL EUTHANIZED AT HIGH 701 00:29:11,920 --> 00:29:13,120 VIRAL LOAD, TIME POINT SHOWS 702 00:29:13,120 --> 00:29:15,320 MUCH LESS BINDING IN THE 703 00:29:15,320 --> 00:29:17,400 BASELINE, THIS ANIMAL WHERE THE 704 00:29:17,400 --> 00:29:19,000 VIRAL LOAD WAS MODERATELY 705 00:29:19,000 --> 00:29:21,000 ELEVATED YOU SEE THERE'S QUITE A 706 00:29:21,000 --> 00:29:23,640 BIT OF BINDING SUGGESTING 707 00:29:23,640 --> 00:29:24,040 NEUROINFLAMMATION. 708 00:29:24,040 --> 00:29:26,560 SO WE CONCLUDED IN THE EARLY 709 00:29:26,560 --> 00:29:28,960 STAGES OF DISEASE WHEN CSF VIRAL 710 00:29:28,960 --> 00:29:37,640 LOADS ARE HIGH MICROGLIAL 711 00:29:37,640 --> 00:29:40,440 INFLAMMATION IS CONVERSELY 712 00:29:40,440 --> 00:29:40,840 CORRELATED. 713 00:29:40,840 --> 00:29:42,560 IMMUNOFLUORESCENCE WAS DONE WITH 714 00:29:42,560 --> 00:29:44,720 DR. MERRICK AT NINDS. 715 00:29:44,720 --> 00:29:49,840 WHEN YOU HAVE VERY HIGH CSF 716 00:29:49,840 --> 00:29:51,440 VIRAL LOAD, THESE MACROPHAGE 717 00:29:51,440 --> 00:29:52,840 STAINS, POOR STAINING OF THESE 718 00:29:52,840 --> 00:29:56,520 CELLS AND A LOT OF APOPTOTIC 719 00:29:56,520 --> 00:29:56,760 MARKERS. 720 00:29:56,760 --> 00:30:00,000 WHEN THE CSL VIRAL LOAD IS 721 00:30:00,000 --> 00:30:01,720 MODERATELY ELEVATED THERE'S 722 00:30:01,720 --> 00:30:03,840 ACTUAL INFLAMMATION, NOT AS MUCH 723 00:30:03,840 --> 00:30:04,320 APOPTOSIS. 724 00:30:04,320 --> 00:30:05,480 THAT CONFIRMED THE FINDINGS THAT 725 00:30:05,480 --> 00:30:07,640 IN THE EARLY STAGES WHEN 726 00:30:07,640 --> 00:30:10,040 PATIENTS HAVE HIGH CSF VIRAL 727 00:30:10,040 --> 00:30:12,360 LOAD IT'S POSSIBLE THERE ISN'T 728 00:30:12,360 --> 00:30:14,960 AS MUCH NEURAL INFLAMMATION AS 729 00:30:14,960 --> 00:30:17,600 MICROGLIAL LOSS, CONSISTENT WITH 730 00:30:17,600 --> 00:30:23,040 SOME WORK WHICH SUGGESTED THAT 731 00:30:23,040 --> 00:30:24,480 MITOCHONDRIA AND ASTROCYTES WHEN 732 00:30:24,480 --> 00:30:29,040 INFECTED, A LOT OF THEM DIED AND 733 00:30:29,040 --> 00:30:31,840 FIVING CELLS BECOME RESERVOIRS. 734 00:30:31,840 --> 00:30:33,040 THIS IS APOPTOSIS. 735 00:30:33,040 --> 00:30:34,640 BUT MORE INTERESTINGLY WE FOUND 736 00:30:34,640 --> 00:30:36,520 THAT NEURONS WERE ALSO DYING. 737 00:30:36,520 --> 00:30:40,240 SO THIS IS A NEURON WITH 738 00:30:40,240 --> 00:30:41,840 APOPTOTIC MARKERS, AND THIS IS 739 00:30:41,840 --> 00:30:44,960 NOT GOING TO COME BACK. 740 00:30:44,960 --> 00:30:48,880 AND, AGAIN, THAT TAKES US BACK 741 00:30:48,880 --> 00:30:51,080 TO EARLY FINDING, NEURONAL LOSS 742 00:30:51,080 --> 00:30:54,440 IN THE BRAIN, AND THAT PROBABLY 743 00:30:54,440 --> 00:30:56,320 ACCOUNTS FOR THIS IRREVERSIBLE 744 00:30:56,320 --> 00:31:00,800 NEURONAL INJURY THAT HAPPENS 745 00:31:00,800 --> 00:31:01,880 AFTER INFECTION AND BEFORE 746 00:31:01,880 --> 00:31:02,840 ANTIRETROVIRAL THERAPY AND DOES 747 00:31:02,840 --> 00:31:03,760 NOT REVERSE. 748 00:31:03,760 --> 00:31:05,840 AGAIN TREATING PATIENTS AS EARLY 749 00:31:05,840 --> 00:31:09,320 AS POSSIBLE IS THE ONLY WAY TO 750 00:31:09,320 --> 00:31:12,240 PREVENT THIS IRREVERSIBLE 751 00:31:12,240 --> 00:31:13,880 DAMAGING FROM HAPPENING. 752 00:31:13,880 --> 00:31:17,240 ANOTHER INTEREST OF OURS WAS 753 00:31:17,240 --> 00:31:18,160 ACTUALLY IMAGING 754 00:31:18,160 --> 00:31:18,680 NEUROTRANSMITTER SYSTEMS. 755 00:31:18,680 --> 00:31:23,200 AND, FOR EXAMPLE, IT'S ALWAYS 756 00:31:23,200 --> 00:31:28,240 BEEN KNOWN DOPE DOPAMINERGIC 757 00:31:28,240 --> 00:31:29,760 SYSTEM IS SUSCEPTIBLE TO HIV, IN 758 00:31:29,760 --> 00:31:37,440 EARLY DAYS OF THE EPIDEMIC 759 00:31:37,440 --> 00:31:38,600 PATIENTS WERE PRESENTING WITH 760 00:31:38,600 --> 00:31:38,840 THIS. 761 00:31:38,840 --> 00:31:40,880 WE WANTED TO SEE HOW THIS IS 762 00:31:40,880 --> 00:31:43,200 RELATED TO VIRAL PROTEIN 763 00:31:43,200 --> 00:31:43,840 NEUROTOXICITY. 764 00:31:43,840 --> 00:31:47,240 SO, WE HAD AN ANIMAL MODEL, HIV 765 00:31:47,240 --> 00:31:50,000 TRANSGENIC RAT, WHICH WE KNEW 766 00:31:50,000 --> 00:31:51,480 HAD A VIRAL PROTEIN EXPRESSION, 767 00:31:51,480 --> 00:31:53,800 AND WE WANTED TO IMAGE THAT 768 00:31:53,800 --> 00:31:55,240 ANIMAL OVER TIME. 769 00:31:55,240 --> 00:31:57,280 HOWEVER, WHEN YOU DEAL WITH 770 00:31:57,280 --> 00:31:58,840 RODENTS, YOU CANNOT REALLY USE A 771 00:31:58,840 --> 00:32:02,720 PET SCANNER BECAUSE PET SCANNERS 772 00:32:02,720 --> 00:32:04,680 HAVE VERY -- WELL, RESOLUTION IS 773 00:32:04,680 --> 00:32:06,040 NOT THAT GREAT. 774 00:32:06,040 --> 00:32:07,640 IT'S 4 TO 5 MILLIMETERS, PERFECT 775 00:32:07,640 --> 00:32:11,040 FOR HUMANS BUT NOT GOOD ENOUGH 776 00:32:11,040 --> 00:32:12,320 FOR SMALL ANIMALS, 4 TO 5 777 00:32:12,320 --> 00:32:13,880 MILLIMETERS IS NOT GOING TO CUT 778 00:32:13,880 --> 00:32:15,240 IT LOOKING FOR A SMALL LESION IN 779 00:32:15,240 --> 00:32:17,840 THE BRAIN OF A RAT, FOR EXAMPLE. 780 00:32:17,840 --> 00:32:19,240 SO, FOR THIS WE USED WHAT WE 781 00:32:19,240 --> 00:32:24,360 REFER TO AS A SMALL ANIMAL 782 00:32:24,360 --> 00:32:26,880 PET-CT SCANNER, THIS WAS 783 00:32:26,880 --> 00:32:30,880 ACTUALLY DEVELOPED HERE AT NIH. 784 00:32:30,880 --> 00:32:33,240 DEPARTMENT OF NUCLEAR MEDICINE. 785 00:32:33,240 --> 00:32:34,800 COURTESY OF MIKE GREEN. 786 00:32:34,800 --> 00:32:38,920 AND IT WAS CALLED ATLAS, SMALL 787 00:32:38,920 --> 00:32:42,320 ANIMAL PET SCANNER, THIS WAS AN 788 00:32:42,320 --> 00:32:45,840 AMAZING INVENTION. 789 00:32:45,840 --> 00:32:48,440 WHICH OTHER TIME, IMPROVEMENT 790 00:32:48,440 --> 00:32:50,000 AND ADVANCED TECHNOLOGY, WITH 791 00:32:50,000 --> 00:32:52,720 DEVELOPMENT OF MUCH SMALLER 792 00:32:52,720 --> 00:32:54,040 DETECTORS, FOR EXAMPLE, AND 793 00:32:54,040 --> 00:32:55,680 LARGER TUBES, WE ENDED UP WITH 794 00:32:55,680 --> 00:32:57,560 MACHINES LIKE THE ONE WE HAVE 795 00:32:57,560 --> 00:33:01,320 HERE AT NIH. 796 00:33:01,320 --> 00:33:05,040 THIS IS OUR MICRO PET-CT SCANNER 797 00:33:05,040 --> 00:33:07,440 WITH HIGHER PHOTON SENSITIVITY, 798 00:33:07,440 --> 00:33:08,560 BETTER ENERGY RESOLUTION, 799 00:33:08,560 --> 00:33:10,400 COINCIDENCE TIME RESOLUTION IS 800 00:33:10,400 --> 00:33:12,800 MUCH BETTER, HAVE BETTER 801 00:33:12,800 --> 00:33:13,880 PERFORMANCE, AND EVENTUALLY 802 00:33:13,880 --> 00:33:15,680 SPATIAL RESOLUTION IS MUCH 803 00:33:15,680 --> 00:33:16,440 BETTER. 804 00:33:16,440 --> 00:33:18,480 FOR THIS MACHINE, FOR EXAMPLE, 805 00:33:18,480 --> 00:33:19,840 IT'S SUPPOSED TO BE .8 806 00:33:19,840 --> 00:33:20,440 MILLIMETERS, IN THE CENTER OF 807 00:33:20,440 --> 00:33:22,360 THE FIELD OF VIEW WHICH IS WAY 808 00:33:22,360 --> 00:33:24,720 BETTER THAN IF YOU COMPARE TO A 809 00:33:24,720 --> 00:33:25,640 BIG PET SCANNER. 810 00:33:25,640 --> 00:33:28,160 AND EVEN WHERE YOU DON'T ACHIEVE 811 00:33:28,160 --> 00:33:29,880 THAT, IT'S STILL IN THE 1 812 00:33:29,880 --> 00:33:31,640 MILLIMETER RANGE, WHICH IS VERY 813 00:33:31,640 --> 00:33:33,800 APPROPRIATE FOR USE IN SMALL 814 00:33:33,800 --> 00:33:34,360 ANIMALS. 815 00:33:34,360 --> 00:33:38,480 SO WE USE THE MICRO PET-CT 816 00:33:38,480 --> 00:33:40,520 SCANNER TO LOOK AT THE SMALL 817 00:33:40,520 --> 00:33:46,920 ANIMAL MODEL OF HIV INFECTION, A 818 00:33:46,920 --> 00:33:47,680 NON-INFECTIOUS MODEL, TRANSGENIC 819 00:33:47,680 --> 00:33:48,800 RAT, EXPRESSION OF VIRAL 820 00:33:48,800 --> 00:33:49,040 PROTEINS. 821 00:33:49,040 --> 00:33:50,760 IN FACT WE HAD TESTED THIS 822 00:33:50,760 --> 00:33:52,640 ANIMAL OVER LONG PERIOD OF TIME, 823 00:33:52,640 --> 00:33:59,480 WE FOUND THAT VIRAL PROTEINS 824 00:33:59,480 --> 00:34:01,000 SPECIFICALLY GP 120 WAS 825 00:34:01,000 --> 00:34:03,520 EXPRESSED IN THE SERUM AND 826 00:34:03,520 --> 00:34:04,240 BRAIN. 827 00:34:04,240 --> 00:34:06,120 WE WERE IMAGING WITH MRI AND WE 828 00:34:06,120 --> 00:34:08,040 NOTICED THEY WERE LOSING VOLUME 829 00:34:08,040 --> 00:34:09,520 OVER TIME, SPECIFICALLY IN THE 830 00:34:09,520 --> 00:34:10,560 BASAL GANGLIA. 831 00:34:10,560 --> 00:34:14,240 SO WE DECIDED TO LOOK AT THE 832 00:34:14,240 --> 00:34:16,240 SPECIFIC STATUS OF THE 833 00:34:16,240 --> 00:34:19,640 DOPAMINERGIC SYSTEM USING PET 834 00:34:19,640 --> 00:34:20,640 SCANNER. 835 00:34:20,640 --> 00:34:22,960 WE USED WHO LIGANDS, FIRST IS 836 00:34:22,960 --> 00:34:27,920 TARGETED AGAINST THE DOPAMINE 837 00:34:27,920 --> 00:34:29,000 TRANSPORTER, PRESYNAPTIC 838 00:34:29,000 --> 00:34:31,040 ASSESSMENT OF THE DOPAMINERGIC 839 00:34:31,040 --> 00:34:32,920 SYSTEM, CORONAL PET SCANS 840 00:34:32,920 --> 00:34:35,360 OVERLAID ON CORONAL MR IMAGES. 841 00:34:35,360 --> 00:34:39,160 YOU CAN SEE THE TRANSGENIC MOUSE 842 00:34:39,160 --> 00:34:41,320 HAS LESS BINDING THAN THE 843 00:34:41,320 --> 00:34:42,040 CONTROL MOUSE. 844 00:34:42,040 --> 00:34:53,920 AND THEN WE USED ANOTHER LIGAND, 845 00:34:53,920 --> 00:34:54,600 F-18-FALLYPRIDE, DECREASE 846 00:34:54,600 --> 00:34:58,080 BINDING COMPARED TO CONTROL 847 00:34:58,080 --> 00:35:00,440 ANIMALS SUGGESTING THIS IS PRE 848 00:35:00,440 --> 00:35:01,360 AND POST SYNAPTIC DOPAMINERGIC 849 00:35:01,360 --> 00:35:02,640 DYSFUNCTION HAPPENING IN THOSE 850 00:35:02,640 --> 00:35:05,040 ANIMALS, LIKELY AS A RESULT OF 851 00:35:05,040 --> 00:35:08,200 EXPOSURE TO VIRAL PROTEINS. 852 00:35:08,200 --> 00:35:09,640 SPECIFICALLY THAT ANIMALS WITH 853 00:35:09,640 --> 00:35:12,800 HIGHER 120 LEVELS WITH ARE THE 854 00:35:12,800 --> 00:35:18,480 ONES THAT SHOWED LOWEST DOPAMINE 855 00:35:18,480 --> 00:35:22,080 TRANSPORTER AND D2/D3 RECEPTOR 856 00:35:22,080 --> 00:35:24,720 DENSITY. 857 00:35:24,720 --> 00:35:27,320 HIV VIRAL PROTEINS ARE 858 00:35:27,320 --> 00:35:28,520 NEUROTOXICS TO DOPAMINERGIC 859 00:35:28,520 --> 00:35:31,360 NEURONS, SHOWING THERE'S LESS 860 00:35:31,360 --> 00:35:33,240 DOPAMINE TRANSPORTER, TYROSINE 861 00:35:33,240 --> 00:35:47,040 HIGH HYDROXYLASE. 862 00:35:47,040 --> 00:35:49,440 IT WAS MOSTLY IN THE OLDER 863 00:35:49,440 --> 00:35:49,760 ANIMALS. 864 00:35:49,760 --> 00:35:55,440 AND WHY IS THIS IMPORTANT? 865 00:35:55,440 --> 00:35:59,760 BECAUSE VIRUS IN THE BRAIN IS 866 00:35:59,760 --> 00:36:01,400 ACTUALLY -- THERE ARE THEORIES 867 00:36:01,400 --> 00:36:02,920 THERE'S STILL PRODUCTION OF 868 00:36:02,920 --> 00:36:05,000 VIRAL PROTEINS EVEN THOUGH THE 869 00:36:05,000 --> 00:36:06,520 PATIENTS ARE TREATED. 870 00:36:06,520 --> 00:36:09,600 DR. AVI NATH AT NINDS HAS SHOWN 871 00:36:09,600 --> 00:36:12,600 THAT THERE'S EXPRESSION IN THE 872 00:36:12,600 --> 00:36:15,200 CSF OF TREATED HIV-POSITIVE 873 00:36:15,200 --> 00:36:17,040 PATIENTS, LIKELY EVEN IF WE'RE 874 00:36:17,040 --> 00:36:18,360 TREATING THOSE PATIENTS THERE 875 00:36:18,360 --> 00:36:20,760 ARE STILL VIRAL PROTEINS, AND 876 00:36:20,760 --> 00:36:22,000 THAT COULD CAUSE WORSENING OF 877 00:36:22,000 --> 00:36:23,400 THE DOPAMINERGIC PATHOLOGY IN 878 00:36:23,400 --> 00:36:24,720 THOSE PATIENTS. 879 00:36:24,720 --> 00:36:27,760 SO, WE TOOK THIS WORK WE DID ON 880 00:36:27,760 --> 00:36:31,440 THE RATS, TRANSLATED IT TO A 881 00:36:31,440 --> 00:36:33,400 HUMAN STUDY, SUPPORTED BY OFFICE 882 00:36:33,400 --> 00:36:35,320 OF AIDS RESEARCH, WE JUST 883 00:36:35,320 --> 00:36:38,280 WRAPPED UP THE IMAGING AND ARE 884 00:36:38,280 --> 00:36:45,640 STARTING ANALYSIS LOOKING AT 885 00:36:45,640 --> 00:36:46,480 DOPAMINERGIC AND SERATONERGIC, 886 00:36:46,480 --> 00:36:48,120 COMPARED TO CONTROLS, SO WE CAN 887 00:36:48,120 --> 00:36:54,040 TELL FOR SURE NOW THAT IF THERE 888 00:36:54,040 --> 00:36:56,000 IS RESIDUAL DOPAMINERGIC AND 889 00:36:56,000 --> 00:37:00,960 SERATONERGIC DYSFUNCTION OR IF 890 00:37:00,960 --> 00:37:01,960 THERE ISN'T. 891 00:37:01,960 --> 00:37:04,360 SHIFTING GEARS, ANOTHER SET OF 892 00:37:04,360 --> 00:37:09,600 DISEASES WHERE MOW WILL -- 893 00:37:09,600 --> 00:37:11,400 MOLECULAR IMAGING IS HELPFUL IS 894 00:37:11,400 --> 00:37:13,440 IN EBOLA FOR EXAMPLE, IN 895 00:37:13,440 --> 00:37:14,640 UNDERDEVELOPED COUNTRIES WITH 896 00:37:14,640 --> 00:37:15,480 LIMITED RESOURCE, DIFFICULT TO 897 00:37:15,480 --> 00:37:24,280 STUDY THEM WHERE THEY OCCUR, 898 00:37:24,280 --> 00:37:25,800 BECAUSE OF THOSE REASONS. 899 00:37:25,800 --> 00:37:27,240 EBOLA, IN THE MIDST OF THE 900 00:37:27,240 --> 00:37:28,640 EPIDEMIC, NOBODY WAS THINKING 901 00:37:28,640 --> 00:37:30,360 LOUDLY ABOUT HOW IT'S AFFECTING 902 00:37:30,360 --> 00:37:31,960 THE BRAIN BECAUSE PATIENTS WERE 903 00:37:31,960 --> 00:37:33,440 DYING OF OTHER REASONS. 904 00:37:33,440 --> 00:37:36,480 BUT THEN AFTER THE EPIDEMIC WAS 905 00:37:36,480 --> 00:37:37,680 UNDER CONTROL, PATIENTS STARTED 906 00:37:37,680 --> 00:37:41,200 COMPLAINING OF WHAT THEY 907 00:37:41,200 --> 00:37:42,240 REFERRED TO AS POST-EBOLAVIRUS 908 00:37:42,240 --> 00:37:44,600 DISEASE SYNDROME, AND THIS IS A 909 00:37:44,600 --> 00:37:47,440 COMPILATION OF SYMPTOMS 910 00:37:47,440 --> 00:37:49,400 INCLUDING FATIGUE, DIFFICULTY 911 00:37:49,400 --> 00:37:50,680 SLEEPING, HEADACHES, ISSUES WITH 912 00:37:50,680 --> 00:37:53,080 MEMORY, WITH MOOD, AS WELL AS 913 00:37:53,080 --> 00:37:54,840 OTHER VISUAL AND AUDITORY 914 00:37:54,840 --> 00:37:55,120 PROBLEMS. 915 00:37:55,120 --> 00:37:58,360 THE QUESTION IS, WHAT EXACTLY IS 916 00:37:58,360 --> 00:37:58,640 HAPPENING? 917 00:37:58,640 --> 00:38:02,360 NOBODY THOUGHT EBOLA COULD 918 00:38:02,360 --> 00:38:04,640 ACTUALLY HAVE DIRECT CNS 919 00:38:04,640 --> 00:38:05,080 EFFECTS. 920 00:38:05,080 --> 00:38:07,840 TO BETTER UNDERSTAND, WE 921 00:38:07,840 --> 00:38:11,080 COLLABORATED WITH INTEGRATIVE 922 00:38:11,080 --> 00:38:13,080 RESEARCH FACILITY, A BSF 4 923 00:38:13,080 --> 00:38:16,240 FACILITY IN FORT DETRICK, 924 00:38:16,240 --> 00:38:18,960 STATE-OF-THE-ART IMAGING 925 00:38:18,960 --> 00:38:24,440 CAPABILITIES. 926 00:38:24,440 --> 00:38:29,240 SO WE COLLABORATED WITH TO IMAGE 927 00:38:29,240 --> 00:38:31,000 RHESUS MACAQUES WITH EBOLA 928 00:38:31,000 --> 00:38:35,480 VIRUS, TO EVALUATE ANIMALS 929 00:38:35,480 --> 00:38:37,880 LONGITUDINALLY, IMAGED AT 930 00:38:37,880 --> 00:38:45,920 BASELINE BEFORE INOCULATIONED, 931 00:38:45,920 --> 00:38:49,440 AND AFTER INOCULATION, 18F-FDG 932 00:38:49,440 --> 00:38:52,320 PET AND MRI WITH T1 MAPPING, TO 933 00:38:52,320 --> 00:38:55,440 SEE IF THERE'S LOSS OF BRAIN 934 00:38:55,440 --> 00:38:56,440 BARRIER INTEGRITY. 935 00:38:56,440 --> 00:38:59,440 WITH FDG PET WHAT WE SAW WAS 936 00:38:59,440 --> 00:39:01,240 EVIDENCE OF INCREASED FDG UPTAKE 937 00:39:01,240 --> 00:39:04,800 IN CERTAIN LOCATIONS IN THE 938 00:39:04,800 --> 00:39:11,840 BRAIN, MOSTLY BRAINSTEM AND 939 00:39:11,840 --> 00:39:12,520 THALAMUS, OVER TIME 940 00:39:12,520 --> 00:39:14,120 SIGNIFICANTLY INCREASED OVER 941 00:39:14,120 --> 00:39:14,840 TIME. 942 00:39:14,840 --> 00:39:19,640 THE REGIONS WHICH WERE MOST 943 00:39:19,640 --> 00:39:21,120 INVOLVED WITH THALAMUS, 944 00:39:21,120 --> 00:39:22,840 MID-BRAIN, PONS. 945 00:39:22,840 --> 00:39:24,600 THAT WAS INTERESTING, 946 00:39:24,600 --> 00:39:28,840 CORRELATIONS WITH VIRAL OR WITH 947 00:39:28,840 --> 00:39:29,760 CYTOKINE LEVELS, BOTH PRO- AND 948 00:39:29,760 --> 00:39:31,400 ANTI-INFLAMMATORY CYTOKINES. 949 00:39:31,400 --> 00:39:33,360 FOR EXAMPLE, THE PONS WAS THE 950 00:39:33,360 --> 00:39:35,000 PART OF THE BRAIN WHICH WAS 951 00:39:35,000 --> 00:39:37,440 MOSTLY INVOLVED, IT WAS ACTUALLY 952 00:39:37,440 --> 00:39:40,040 ALSO THE FINDINGS WERE 953 00:39:40,040 --> 00:39:43,000 CORRELATED WITH PLASMA VIRAL 954 00:39:43,000 --> 00:39:45,360 LOAD AND INTERLEUKIN 10, 955 00:39:45,360 --> 00:39:45,960 ASSUMING INFLAMMATORY PROCESS 956 00:39:45,960 --> 00:39:49,040 THAT COULD ACCOUNT FOR THIS 957 00:39:49,040 --> 00:39:50,000 INCREASED ACTIVITY AND INDEED 958 00:39:50,000 --> 00:39:51,560 WERE ABLE TO SHOW EARLY 959 00:39:51,560 --> 00:39:53,040 INFLAMMATION IN BRAINS OF THOSE 960 00:39:53,040 --> 00:39:53,600 ANIMALS. 961 00:39:53,600 --> 00:40:01,800 SO AGAIN THIS IS THE 962 00:40:01,800 --> 00:40:03,040 COLLABORATION WITH DR. NATH, YOU 963 00:40:03,040 --> 00:40:05,840 CAN SEE THE CELLS ARE STARTING 964 00:40:05,840 --> 00:40:10,640 TO GET LARGER, PROCESSES ARE 965 00:40:10,640 --> 00:40:18,240 SHORTER. 966 00:40:18,240 --> 00:40:19,200 PROBABLY BECAUSE ANIMALS DID NOT 967 00:40:19,200 --> 00:40:20,760 SURVIVE LONG ENOUGH FOR THAT TO 968 00:40:20,760 --> 00:40:21,080 DEVELOP. 969 00:40:21,080 --> 00:40:23,360 THIS IS PROBABLY ONE OF THE 970 00:40:23,360 --> 00:40:24,840 REASONS WE'RE SEEING THIS 971 00:40:24,840 --> 00:40:27,160 INCREASED UPTAKE. 972 00:40:27,160 --> 00:40:29,040 WE ALSO LOOKED MORE CAREFULLY 973 00:40:29,040 --> 00:40:32,520 AND WE NOTICED THERE WAS -- 974 00:40:32,520 --> 00:40:33,640 THERE WERE GROUPS OF NEURONS 975 00:40:33,640 --> 00:40:38,120 SPECIFICALLY IN THE SAME 976 00:40:38,120 --> 00:40:40,320 LOCATIONS, BRAINSTEM AND 977 00:40:40,320 --> 00:40:45,240 THALAMI, STAINING FOR THE EBOLA 978 00:40:45,240 --> 00:40:46,040 VIRUS ANTIGEN, VP-40. 979 00:40:46,040 --> 00:40:48,520 THIS IS THE NEURONAL MARKER. 980 00:40:48,520 --> 00:40:53,960 A LOT WERE APOPTOTIC WHEN 981 00:40:53,960 --> 00:40:54,320 STAINED. 982 00:40:54,320 --> 00:40:55,840 SO BUT WHAT WAS INTERESTING, WE 983 00:40:55,840 --> 00:40:59,480 ASSUMED THEY ARE BEING INFECTED, 984 00:40:59,480 --> 00:41:00,880 PROBABLY UNDERGOING APOPTOSIS, 985 00:41:00,880 --> 00:41:05,240 BUT WHAT WAS REALLY INTERESTING 986 00:41:05,240 --> 00:41:06,960 IS THAT THEY WERE ALSO 987 00:41:06,960 --> 00:41:07,720 UPREGULATING GLUCOSE 988 00:41:07,720 --> 00:41:08,160 TRANSPORTERS. 989 00:41:08,160 --> 00:41:11,760 LOOK AT CELLS INVOLVED, THERE'S 990 00:41:11,760 --> 00:41:13,400 INCREASED GLUT-3 STAINING IN 991 00:41:13,400 --> 00:41:15,160 THOSE CELLS COMPARED TO CELLS 992 00:41:15,160 --> 00:41:15,760 NOT INVOLVED. 993 00:41:15,760 --> 00:41:19,480 WHICH COULD BE THAT THERE'S AN 994 00:41:19,480 --> 00:41:20,680 INCREASE IN GLUCOSE AND FDG 995 00:41:20,680 --> 00:41:23,840 UPTAKE IN THIS STATE OF 996 00:41:23,840 --> 00:41:24,640 APOPTOSIS THAT COULD BE 997 00:41:24,640 --> 00:41:25,840 ACCOUNTING PARTIALLY AT LEAST 998 00:41:25,840 --> 00:41:29,320 FOR THAT FDG UPTAKE THAT WE SAW 999 00:41:29,320 --> 00:41:30,360 IN THE ANIMALS. 1000 00:41:30,360 --> 00:41:36,440 THE SECOND PART OF THE 1001 00:41:36,440 --> 00:41:37,680 EXPERIMENT WAS LOOKING AT THE 1002 00:41:37,680 --> 00:41:41,640 WAY THE BRAIN IS BEHAVING AFTER 1003 00:41:41,640 --> 00:41:42,760 INOCULATION, USING T1 MAPPING. 1004 00:41:42,760 --> 00:41:45,080 SO FIRST WE DID MR IMAGING, 1005 00:41:45,080 --> 00:41:48,720 THERE WEREN'T REALLY ANY MAJOR 1006 00:41:48,720 --> 00:41:51,000 ABNORMALITIES WE COULD DETECT. 1007 00:41:51,000 --> 00:41:53,280 DECIDED TO PURSUE T1 MAPPING, 1008 00:41:53,280 --> 00:41:54,160 YOU CAN ACTUALLY DETECT CONTRAST 1009 00:41:54,160 --> 00:42:00,640 IN THE BRAIN AND YOU CAN DETECT 1010 00:42:00,640 --> 00:42:01,840 THE CONSISTENCY, TISSUE 1011 00:42:01,840 --> 00:42:05,240 CONSISTENCY WITHIN EACH VOXEL. 1012 00:42:05,240 --> 00:42:07,240 THE REASON IS T1 RELAXATION 1013 00:42:07,240 --> 00:42:08,240 VALUES DIVERSITY BETWEEN 1014 00:42:08,240 --> 00:42:10,840 DIFFERENT COMPONENTS IN THE 1015 00:42:10,840 --> 00:42:13,320 BRAIN, FOR EXAMPLE, AT 3 TESLA 1016 00:42:13,320 --> 00:42:14,320 FLUID HAS LONG RELAXATION TIME. 1017 00:42:14,320 --> 00:42:16,640 IF YOU HAVE A VOXEL WHICH HAS 1018 00:42:16,640 --> 00:42:24,680 MORE FLUID IN IT, T1 VALUES GO 1019 00:42:24,680 --> 00:42:24,840 UP. 1020 00:42:24,840 --> 00:42:29,720 WE GAVE CONTRAST, WANTED TO LOOK 1021 00:42:29,720 --> 00:42:36,080 AT THE PARAMAGNETIC EFFECTS OF 1022 00:42:36,080 --> 00:42:38,800 GADOLINIUM, IF YOU HAVE CONTRAST 1023 00:42:38,800 --> 00:42:40,440 THAT'S LEAKING ACROSS THE 1024 00:42:40,440 --> 00:42:42,960 BLOOD-BRAIN BARRIER YOU SEND UP 1025 00:42:42,960 --> 00:42:45,360 WITH MORE GADOLINIUM, MORE T1 1026 00:42:45,360 --> 00:42:46,560 SHORTENING, DROP IN 1027 00:42:46,560 --> 00:42:47,760 POST-CONTRAST VALUES WILL ARE 1028 00:42:47,760 --> 00:42:48,840 MORE INTENSE. 1029 00:42:48,840 --> 00:42:51,920 WE USE THE TWO APPROACHES TO 1030 00:42:51,920 --> 00:42:53,800 IMAGE THE ANIMALS AT BASELINE, 1031 00:42:53,800 --> 00:42:57,080 AS WELL AS AFTER INOCULATION. 1032 00:42:57,080 --> 00:43:00,240 AND WE FOUND THAT THERE WAS 1033 00:43:00,240 --> 00:43:01,960 ACTUALLY EVIDENCE OF EDEMA IN 1034 00:43:01,960 --> 00:43:03,240 THE BRAIN. 1035 00:43:03,240 --> 00:43:06,840 IT'S REALLY SUBTLE, BECAUSE T1 1036 00:43:06,840 --> 00:43:07,960 VALUES WERE INCREASING. 1037 00:43:07,960 --> 00:43:11,280 AND IN THE TWO REGIONS, 1038 00:43:11,280 --> 00:43:11,840 STATISTICALLY SIGNIFICANT. 1039 00:43:11,840 --> 00:43:13,840 IF YOU LOOK AT THE MAPS YOU CAN 1040 00:43:13,840 --> 00:43:15,840 SEE THE T1 VALUES ARE INCREASING 1041 00:43:15,840 --> 00:43:19,080 A LITTLE BIT IN CERTAIN 1042 00:43:19,080 --> 00:43:19,440 LOCATIONS. 1043 00:43:19,440 --> 00:43:20,640 SUGGESTING THERE'S MORE FLUID IN 1044 00:43:20,640 --> 00:43:21,720 THE BRAIN. 1045 00:43:21,720 --> 00:43:25,840 AND WHEN WE GAVE CONTRAST, WE 1046 00:43:25,840 --> 00:43:28,240 HAD FURTHER EXACERBATION OF DROP 1047 00:43:28,240 --> 00:43:30,480 IN T1 VALUES SUGGESTING THERE'S 1048 00:43:30,480 --> 00:43:32,440 BEEN LEAKAGE OF CONTRAST INTO 1049 00:43:32,440 --> 00:43:34,160 THE EXTRACELLULAR SPACE AS WELL. 1050 00:43:34,160 --> 00:43:39,440 ALL OF THESE VALUES CORRELATED 1051 00:43:39,440 --> 00:43:40,480 WITH VIREMIA AND CYTOKINES. 1052 00:43:40,480 --> 00:43:42,480 IF YOU HAVE A LOT OF 1053 00:43:42,480 --> 00:43:43,600 INFLAMMATION IN THE PERIPHERY 1054 00:43:43,600 --> 00:43:45,240 AND IN THE BRAIN, THAT ACTUALLY 1055 00:43:45,240 --> 00:43:48,480 IS ONE OF THE CONTRIBUTORS TO 1056 00:43:48,480 --> 00:43:49,120 BLOOD-BRAIN BARRIER DYSFUNCTION 1057 00:43:49,120 --> 00:43:52,040 ALONG WITH THE FACT THAT EBOLA 1058 00:43:52,040 --> 00:43:53,640 VIRUS INFECTS ENDOTHELIAL CELLS. 1059 00:43:53,640 --> 00:43:57,880 SO, OBVIOUSLY WE HAD TO GO BACK 1060 00:43:57,880 --> 00:44:02,440 TO DRAGON AND LABELED -- WE 1061 00:44:02,440 --> 00:44:03,640 STAINED THE BRAINS OF THE 1062 00:44:03,640 --> 00:44:05,440 ANIMALS TO SEE IF THERE'S 1063 00:44:05,440 --> 00:44:06,680 LEAKAGE OF ALBUMIN, THAT'S WHAT 1064 00:44:06,680 --> 00:44:08,320 WE FOUND. 1065 00:44:08,320 --> 00:44:11,080 THESE AREAS OF -- GREEN AREAS 1066 00:44:11,080 --> 00:44:14,800 ARE AREAS OF ALBUMIN 1067 00:44:14,800 --> 00:44:16,440 ACCUMULATION IN THE BRAIN, THE 1068 00:44:16,440 --> 00:44:18,760 PROTEIN IS NOT SUPPOSED TO CROSS 1069 00:44:18,760 --> 00:44:19,840 INTACT BLOOD-BRAIN BARRIER. 1070 00:44:19,840 --> 00:44:22,920 IF IT DOES, IT INDICATES THAT 1071 00:44:22,920 --> 00:44:25,040 THERE IS A DISRUPTION. 1072 00:44:25,040 --> 00:44:28,360 ALBUMIN IS NEURO TOXIC, AS WELL 1073 00:44:28,360 --> 00:44:29,760 AS MANY OTHER POTENTIAL 1074 00:44:29,760 --> 00:44:30,760 MOLECULES THAT HAVE CROSSED THE 1075 00:44:30,760 --> 00:44:32,480 BLOOD-BRAIN BARRIER AT THAT 1076 00:44:32,480 --> 00:44:33,920 POINT AND COULD HAVE CAUSED 1077 00:44:33,920 --> 00:44:35,040 NEURONAL LOSS. 1078 00:44:35,040 --> 00:44:37,880 SOME NEURONS WE FOUND TO BE 1079 00:44:37,880 --> 00:44:38,440 APOPTOTIC STAINED GREEN, 1080 00:44:38,440 --> 00:44:41,040 SUGGESTING THAT THEY WERE 1081 00:44:41,040 --> 00:44:42,640 ACTUALLY TAKING ALBUMIN IN. 1082 00:44:42,640 --> 00:44:46,480 SO, WE THINK THAT THIS ALONG 1083 00:44:46,480 --> 00:44:47,360 WITH NEUROINFLAMMATORY CHANGES 1084 00:44:47,360 --> 00:44:49,720 COULD BE -- COULD ACCOUNT AT 1085 00:44:49,720 --> 00:44:51,400 LEAST PARTIALLY FOR THE 1086 00:44:51,400 --> 00:44:52,640 NEUROLOGIC SYMPTOMS WE'RE SEEING 1087 00:44:52,640 --> 00:44:53,600 IN SURVIVORS. 1088 00:44:53,600 --> 00:44:55,120 SPECIFICALLY THAT A LOT OF 1089 00:44:55,120 --> 00:44:56,640 SYMPTOMS OF THE SURVIVORS 1090 00:44:56,640 --> 00:44:58,280 CORRELATE WITH OR ARE ACTUALLY 1091 00:44:58,280 --> 00:45:03,640 CORRESPONDING TO DEFICITS IN THE 1092 00:45:03,640 --> 00:45:05,440 BRAINSTEM AND THE SUBCORTICAL 1093 00:45:05,440 --> 00:45:05,920 STRUCTURES. 1094 00:45:05,920 --> 00:45:08,440 THE QUESTION IS WHETHER OTHER 1095 00:45:08,440 --> 00:45:09,840 VIRAL INFECTIONS LIKE COVID FOR 1096 00:45:09,840 --> 00:45:11,480 EXAMPLE COULD ACTUALLY BE 1097 00:45:11,480 --> 00:45:12,960 ASSOCIATED WITH SIMILAR PROCESS. 1098 00:45:12,960 --> 00:45:14,960 THERE HAS BEEN A LOT OF WORK ON 1099 00:45:14,960 --> 00:45:16,480 COVID AND TRYING TO UNDERSTAND 1100 00:45:16,480 --> 00:45:20,840 WHAT'S HAPPENING IN THE BRAIN OF 1101 00:45:20,840 --> 00:45:22,480 SURVIVORS INFECTED, NICE REVIEW 1102 00:45:22,480 --> 00:45:28,520 RECENTLY BY DR. NATH ABOUT 1103 00:45:28,520 --> 00:45:29,720 POTENTIAL CAUSES OF CNS ISSUES 1104 00:45:29,720 --> 00:45:32,240 IN COVID PATIENTS BUT AT LEAST 1105 00:45:32,240 --> 00:45:35,040 IN ONE STUDY THERE WAS EVIDENCE 1106 00:45:35,040 --> 00:45:36,440 OF LEAKAGE OF PROTEINS IN THE 1107 00:45:36,440 --> 00:45:38,440 BRAIN OF THOSE PATIENTS. 1108 00:45:38,440 --> 00:45:40,560 SO WHETHER THIS CONTRIBUTES TO 1109 00:45:40,560 --> 00:45:44,720 THEIR SYMPTOMS OR NOT, IT'S 1110 00:45:44,720 --> 00:45:45,480 STILL REALLY NOT ANSWERED. 1111 00:45:45,480 --> 00:45:47,360 STILL NEED TO DO MORE WORK TO 1112 00:45:47,360 --> 00:45:48,840 FIGURE THAT ONE OUT. 1113 00:45:48,840 --> 00:45:49,960 SO, THE LAST EXAMPLE I'M GOING 1114 00:45:49,960 --> 00:45:55,120 TO GIVE IS HOW YOU COULD USE 1115 00:45:55,120 --> 00:45:56,800 ADVANCED MR IMAGING TO ASSESS 1116 00:45:56,800 --> 00:46:00,080 TREATMENT EFFECT, WORK IN 1117 00:46:00,080 --> 00:46:01,840 COLLABORATION WITH DR. PIERCE 1118 00:46:01,840 --> 00:46:06,120 AND DR. MILLER, AT NIAID, 1119 00:46:06,120 --> 00:46:08,400 CEREBRAL MALARIA IS A DISEASE 1120 00:46:08,400 --> 00:46:10,360 THAT OCCURS IN CHILDREN A LOT, 1121 00:46:10,360 --> 00:46:12,640 MOSTLY LESS THAN 5 YEARS OLD. 1122 00:46:12,640 --> 00:46:13,760 UNFORTUNATELY, IT'S ASSOCIATED 1123 00:46:13,760 --> 00:46:16,920 WITH SEVERE MORBIDITY AND 1124 00:46:16,920 --> 00:46:17,400 MORTALITY. 1125 00:46:17,400 --> 00:46:21,080 AND IT'S OBVIOUSLY AN ENDEMIC 1126 00:46:21,080 --> 00:46:24,760 AREAS, WITH NOT A LOT OF 1127 00:46:24,760 --> 00:46:25,480 RESOURCES, THE PATHOPHYSIOLOGY 1128 00:46:25,480 --> 00:46:26,640 OF DISEASE IS NOT VERY WELL 1129 00:46:26,640 --> 00:46:28,640 UNDERSTOOD BUT WE DO KNOW FOR 1130 00:46:28,640 --> 00:46:30,280 SURE THERE'S EDEMA, IT'S NOT 1131 00:46:30,280 --> 00:46:36,080 LIKE EBOLA WHERE IT'S VERY MILD. 1132 00:46:36,080 --> 00:46:38,040 IN THESE PATIENTS EDEMA, THEY 1133 00:46:38,040 --> 00:46:40,800 GET BRAIN SWELLING, HERNIATE AND 1134 00:46:40,800 --> 00:46:41,120 DIE. 1135 00:46:41,120 --> 00:46:46,120 THE PROPOSED CAUSE IS GLUTAMATE 1136 00:46:46,120 --> 00:46:46,480 EXCITEOTOXICITY. 1137 00:46:46,480 --> 00:46:48,440 THE REASON WE STARTED THIS 1138 00:46:48,440 --> 00:46:52,160 PROJECT, THERE WAS A NEW 1139 00:46:52,160 --> 00:46:54,000 ADJUVANT THERAPY, PROPOSED TO 1140 00:46:54,000 --> 00:46:56,000 REVERSE DISEASE MANIFESTATIONS 1141 00:46:56,000 --> 00:46:58,040 IN INFECTED MOUSE MODELS. 1142 00:46:58,040 --> 00:47:01,200 INFECTED MOUSE MODELS USED FOR 1143 00:47:01,200 --> 00:47:04,440 MALARIA IS EXPERIMENTAL CM, CAN 1144 00:47:04,440 --> 00:47:06,840 WE USE MRI WITH QUANTIFICATION 1145 00:47:06,840 --> 00:47:08,200 TO ASSESS DISEASE PROGRESSION 1146 00:47:08,200 --> 00:47:11,240 AND RESPONSE TO TREATMENT WITH 1147 00:47:11,240 --> 00:47:11,960 GLUTAMINE ANTAGONISTS, THAT'S 1148 00:47:11,960 --> 00:47:14,840 EXACTLY WHAT WE DID. 1149 00:47:14,840 --> 00:47:17,600 WE STARTED BY IMAGING INFECTED 1150 00:47:17,600 --> 00:47:18,720 ANIMALS, CORONAL IMAGES, WE 1151 00:47:18,720 --> 00:47:25,000 PERFORMED THIS WORK AT THE MOUSE 1152 00:47:25,000 --> 00:47:27,040 IMAGING FACILITY, USED 9.4 TESLA 1153 00:47:27,040 --> 00:47:27,640 SCANNER. 1154 00:47:27,640 --> 00:47:33,640 YOU CAN SEE THERE EDEMA IN THE 1155 00:47:33,640 --> 00:47:35,600 OLFACTORY BULBS, IN THE STERNAL 1156 00:47:35,600 --> 00:47:42,160 CAPSULES, WHICH WE WERE ABLE TO 1157 00:47:42,160 --> 00:47:46,000 QUANTIFY AND ALSO MEASURED ADC 1158 00:47:46,000 --> 00:47:47,720 VALUES, DIFFUSION IMAGING, THESE 1159 00:47:47,720 --> 00:47:55,000 INDICATE WHETHER THERE'S EDEMA, 1160 00:47:55,000 --> 00:48:01,960 INCREASE IN ADC VALUES 1161 00:48:01,960 --> 00:48:04,240 SUGGESTING THIS IS FHASOGENIC. 1162 00:48:04,240 --> 00:48:10,360 THERE WAS LEAKAGE OF CONTRAST IN 1163 00:48:10,360 --> 00:48:13,640 CORPUS CALLOSUM AND EXTERNAL CAP 1164 00:48:13,640 --> 00:48:14,280 SUPERVISORS. 1165 00:48:14,280 --> 00:48:16,920 WE DOCUMENTED BLOOD-BRAIN 1166 00:48:16,920 --> 00:48:17,480 BARRIER DYSFUNCTION, IMAGING 1167 00:48:17,480 --> 00:48:18,120 LONGITUDINALLY BEFORE AND AFTER 1168 00:48:18,120 --> 00:48:19,520 TREATMENT, THAT'S ONE OF THE 1169 00:48:19,520 --> 00:48:21,400 GREATEST THINGS ABOUT MOLECULAR 1170 00:48:21,400 --> 00:48:23,600 IMAGING, CAN YOU DO LONGITUDINAL 1171 00:48:23,600 --> 00:48:24,040 IMAGING. 1172 00:48:24,040 --> 00:48:27,840 EACH ANIMAL WILL BE ITS OWN 1173 00:48:27,840 --> 00:48:28,040 CONTROL. 1174 00:48:28,040 --> 00:48:32,760 SO, WE ALLOWED THE ANIMALS TO 1175 00:48:32,760 --> 00:48:35,480 PROGRESS TO BECOME SICK, AND 1176 00:48:35,480 --> 00:48:37,280 THEN WE TREATED THEM AND IMAGING 1177 00:48:37,280 --> 00:48:37,880 THEM AGAIN. 1178 00:48:37,880 --> 00:48:45,560 AND AS YOU CAN SEE HERE THIS IS 1179 00:48:45,560 --> 00:48:47,200 DAY 12 POST-TREATMENT, WERE ABLE 1180 00:48:47,200 --> 00:48:51,480 TO SHOW RESOLUTION OF EDEMA AND 1181 00:48:51,480 --> 00:48:54,840 PHOTOACCUMULATION IN THE BRAIN 1182 00:48:54,840 --> 00:48:57,360 AND MEASURED THIS 1183 00:48:57,360 --> 00:49:05,000 QUANTITATIVELY, AGAIN RELAXED 1184 00:49:05,000 --> 00:49:10,240 MEASURING TISSUE CONSISTENCY, 1185 00:49:10,240 --> 00:49:15,880 RESOLUTION OF CONTRAST SEEN 1186 00:49:15,880 --> 00:49:18,000 BEFORE TREATMENT. 1187 00:49:18,000 --> 00:49:21,520 CAN WE VISUALIZE AND QUANTIFY? 1188 00:49:21,520 --> 00:49:23,360 THE ANSWER IS YES. 1189 00:49:23,360 --> 00:49:25,840 THIS IS ANOTHER PROTEIN THAT'S 1190 00:49:25,840 --> 00:49:35,640 NOT SUPPOSED TO BE IN THE BRAIN 1191 00:49:35,640 --> 00:49:37,680 PARENCHYMA, WE SAW SOME AREAS OF 1192 00:49:37,680 --> 00:49:42,440 HEM ACKNOWLEDGE -- HEMORRHAGE IN 1193 00:49:42,440 --> 00:49:44,920 THOSE ANIMALS. 1194 00:49:44,920 --> 00:49:48,400 CONCLUSION, USING THE MODEL WITH 1195 00:49:48,400 --> 00:49:49,600 SIMILAR CHARACTERISTICS TO HUMAN 1196 00:49:49,600 --> 00:49:52,880 DISEASE, WE KNOW THERE'S EDEMA, 1197 00:49:52,880 --> 00:49:58,680 IN THE ANIMAL THERE'S EDEEMA WE 1198 00:49:58,680 --> 00:50:01,200 REVERSED WITH ANTAGONISTS, THIS 1199 00:50:01,200 --> 00:50:03,160 COULD POTENTIALLY BE USED TO 1200 00:50:03,160 --> 00:50:05,240 TREAT CEREBRAL MALARIA IN 1201 00:50:05,240 --> 00:50:06,560 TREATMENT, POST CLINICAL 1202 00:50:06,560 --> 00:50:06,840 TRANSLATION. 1203 00:50:06,840 --> 00:50:08,000 THAT HASN'T HAPPENED YET BUT 1204 00:50:08,000 --> 00:50:09,640 IT'S SOMETHING THAT IS 1205 00:50:09,640 --> 00:50:10,920 SUPPORTIVE OF THE POTENTIAL OF 1206 00:50:10,920 --> 00:50:13,800 USING THESE DRUGS FOR SUCH A 1207 00:50:13,800 --> 00:50:18,040 HORRIFIC DISEASE. 1208 00:50:18,040 --> 00:50:20,160 SO, WHAT'S THE FUTURE? 1209 00:50:20,160 --> 00:50:22,280 THERE'S MUCH MORE TO MOLECULAR 1210 00:50:22,280 --> 00:50:24,040 IMAGING THAN TRYING TO 1211 00:50:24,040 --> 00:50:25,920 UNDERSTAND PATHOPHYSIOLOGY AND 1212 00:50:25,920 --> 00:50:26,840 IMAGE TREATMENT EFFECT. 1213 00:50:26,840 --> 00:50:28,720 PERHAPS THE HOLY GRAIL IS TO GET 1214 00:50:28,720 --> 00:50:32,120 TO A POINT WHERE WE HAVE LIGANDS 1215 00:50:32,120 --> 00:50:34,000 THAT CAN TELL US EXACTLY WHAT 1216 00:50:34,000 --> 00:50:37,440 THE PATHOGEN IS, THAT'S WHAT 1217 00:50:37,440 --> 00:50:41,520 REREFER TO AS PATHOGEN-SPECIFIC 1218 00:50:41,520 --> 00:50:44,600 IMAGING. 1219 00:50:44,600 --> 00:50:45,680 THIS MOLECULAR IMAGING FIELD IS 1220 00:50:45,680 --> 00:50:46,760 GROWING A LOT. 1221 00:50:46,760 --> 00:50:48,720 LAST TEN YEARS WAY MORE PEOPLE 1222 00:50:48,720 --> 00:50:50,960 INTERESTED IN DEVELOPING LIGANDS 1223 00:50:50,960 --> 00:50:52,440 THAT TARGET SPECIFIC PATHOGENS. 1224 00:50:52,440 --> 00:51:01,240 PERHAPS THE MOST FAMOUS ONE IS 1225 00:51:01,240 --> 00:51:02,040 F-18 FLUORO DEOXY SORBITOL, 1226 00:51:02,040 --> 00:51:08,800 FOUND TO BE A GOOD LIGAND FOR 1227 00:51:08,800 --> 00:51:18,000 GRAM NEGATIVE BACTERIA, 1228 00:51:18,000 --> 00:51:19,040 ENTEROBACKTERALIS. 1229 00:51:19,040 --> 00:51:21,680 WE COLLABORATED AND DEVELOPED 1230 00:51:21,680 --> 00:51:28,800 ANIMAL MODELS OF ASPERGILLUS AND 1231 00:51:28,800 --> 00:51:33,320 BACTERIAL INFECTION, FDS IS A 1232 00:51:33,320 --> 00:51:34,040 GOOD LIGAND FOR 1233 00:51:34,040 --> 00:51:34,440 ENTEROBACKTERALIS. 1234 00:51:34,440 --> 00:51:36,120 THERE ARE MANY OTHER LIGANDS 1235 00:51:36,120 --> 00:51:37,760 THAT ARE BEING DEVELOPED, MOST 1236 00:51:37,760 --> 00:51:43,560 OF WHICH ARE ACTUALLY DEVELOPED 1237 00:51:43,560 --> 00:51:46,280 FOR BACTERIAL INFECTIONS. 1238 00:51:46,280 --> 00:51:49,200 BY DIFFERENT GROUPS, STANFORD, U 1239 00:51:49,200 --> 00:51:51,120 PENN, UCSF, DIFFERENT PLACES. 1240 00:51:51,120 --> 00:51:53,640 WE ARE -- MY LAB, WE'RE 1241 00:51:53,640 --> 00:51:54,640 INTERESTED IN FUNGAL INFECTION, 1242 00:51:54,640 --> 00:51:56,360 AND THAT'S WHY WE'VE DEVELOPED 1243 00:51:56,360 --> 00:52:00,240 ALL THESE FUNGAL INFECTION 1244 00:52:00,240 --> 00:52:09,520 MODELS INCLUDING IV INFECTION, 1245 00:52:09,520 --> 00:52:10,200 DEVELOPING CNS, 1246 00:52:10,200 --> 00:52:12,360 ASPERGILLOMAOSIS, WE HAVE TWO 1247 00:52:12,360 --> 00:52:15,840 APPROACHES TO USING THIS, FIRST 1248 00:52:15,840 --> 00:52:16,960 WE'RE USING SUBSTRATE SIMILAR TO 1249 00:52:16,960 --> 00:52:19,600 THE WAY SORBITOL WAS FOUND TO BE 1250 00:52:19,600 --> 00:52:21,920 GOOD FOR GRAM NEGATIVE BACTERIA, 1251 00:52:21,920 --> 00:52:24,840 WE'RE TRYING TO FIND SUBSTRATES 1252 00:52:24,840 --> 00:52:28,880 PREFERRED BY FUNGI, AND LABEL 1253 00:52:28,880 --> 00:52:30,640 THOSE SUBSTRATES, MOSTLY SUGARS, 1254 00:52:30,640 --> 00:52:31,640 AND INJECT THEM IN OUR ANIMAL 1255 00:52:31,640 --> 00:52:35,400 MODELS AND SEE IF WE CAN HAVE 1256 00:52:35,400 --> 00:52:36,680 SPECIFIC UPTAKE BY FUNGI. 1257 00:52:36,680 --> 00:52:38,920 AND EVENTUALLY IF WE FIND ONE OF 1258 00:52:38,920 --> 00:52:41,120 THOSE WE HAVE QUITE A FEW 1259 00:52:41,120 --> 00:52:42,000 CONTENDERS, THOSE COULD 1260 00:52:42,000 --> 00:52:43,440 POTENTIALLY BE TRANSLATED TO 1261 00:52:43,440 --> 00:52:44,840 HUMAN USE AND BECAUSE THEY ARE 1262 00:52:44,840 --> 00:52:48,120 SUGARS THEY ARE MORE OR LESS 1263 00:52:48,120 --> 00:52:48,960 EASILY TRANSLATED. 1264 00:52:48,960 --> 00:52:51,280 THE OTHER APPROACH WE'RE DOING 1265 00:52:51,280 --> 00:52:53,800 IS BY TARGETING CELL WALL 1266 00:52:53,800 --> 00:52:58,440 COMPONENTS OF FUNGI. 1267 00:52:58,440 --> 00:53:01,280 WE KNOW THEY ARE PRESENT IN THE 1268 00:53:01,280 --> 00:53:03,160 WALL AND NOT IN MAMMALIAN CELLS, 1269 00:53:03,160 --> 00:53:05,920 IF WE TARGET WITH ANTIBODIES OR 1270 00:53:05,920 --> 00:53:06,400 ANTIBODY FRAGMENTS OR 1271 00:53:06,400 --> 00:53:16,000 NANOBODIES, WE MIGHT BE ABLE TO 1272 00:53:16,000 --> 00:53:16,400 ACTUALLY DIAGNOSE 1273 00:53:16,400 --> 00:53:17,160 ASPERGILLUSOSIS IN VIVO. 1274 00:53:17,160 --> 00:53:19,560 WE'RE IN THE EARLY STAGES OF 1275 00:53:19,560 --> 00:53:21,080 TESTING MULTIPLE LIGANDS, WE 1276 00:53:21,080 --> 00:53:22,840 HAVE SOME EARLY SUCCESSES, AND 1277 00:53:22,840 --> 00:53:24,480 WE'RE HOPING THAT ONCE WE 1278 00:53:24,480 --> 00:53:25,240 VALIDATE LIGANDS IN THE 1279 00:53:25,240 --> 00:53:26,640 PRIVILEGE WHICH WE CAN GO TO THE 1280 00:53:26,640 --> 00:53:26,840 BRAIN. 1281 00:53:26,840 --> 00:53:28,760 THE BRAIN IS A LITTLE BIT MORE 1282 00:53:28,760 --> 00:53:31,160 TRICKY BECAUSE WHEN YOU HAVE 1283 00:53:31,160 --> 00:53:32,600 INFECTION AND YOU HAVE 1284 00:53:32,600 --> 00:53:33,360 BLOOD-BRAIN BARRIER OBSTRUCTION 1285 00:53:33,360 --> 00:53:35,000 YOU HAVE TO MAKE SURE WHAT 1286 00:53:35,000 --> 00:53:40,880 YOU'RE LOOKING AT IS NOT 1287 00:53:40,880 --> 00:53:41,240 LEAKAGE. 1288 00:53:41,240 --> 00:53:41,800 THIS IS LEAKAGE ACROSS THE 1289 00:53:41,800 --> 00:53:44,920 BLOOD-BRAIN BARRIER SO WE HAVE 1290 00:53:44,920 --> 00:53:48,480 TO DO SPECIAL STUDIES TO MAKE 1291 00:53:48,480 --> 00:53:50,760 SURE WE SPECIFIC UPTAKE. 1292 00:53:50,760 --> 00:53:52,040 SO IN CONCLUSION, MOLECULAR 1293 00:53:52,040 --> 00:53:53,640 IMAGING CAN BE VERY INSTRUMENTAL 1294 00:53:53,640 --> 00:53:56,560 IN EVALUATION OF CNS INFECTIONS, 1295 00:53:56,560 --> 00:53:57,640 ONCOLOGY WORLD HAS DISCOVERED 1296 00:53:57,640 --> 00:53:59,440 THIS MUCH EARLIER THAN WE DID. 1297 00:53:59,440 --> 00:54:02,520 THERE'S A LOT OF CANCER RESEARCH 1298 00:54:02,520 --> 00:54:03,040 HAPPENING WITH MOLECULAR 1299 00:54:03,040 --> 00:54:04,520 IMAGING, NOT AS MUCH WITH 1300 00:54:04,520 --> 00:54:05,640 INFLAMMATION AND INFECTION. 1301 00:54:05,640 --> 00:54:09,640 BUT AS I SAID, YOU CAN USE THOSE 1302 00:54:09,640 --> 00:54:11,280 TECHNIQUES TO BETTER UNDERSTAND 1303 00:54:11,280 --> 00:54:13,120 DISEASE PATHOPHYSIOLOGY, AS I 1304 00:54:13,120 --> 00:54:14,760 SHOWED WITH HIV, ASSESSING 1305 00:54:14,760 --> 00:54:15,640 LONG-TERM SEQUELAE OF INFECTION 1306 00:54:15,640 --> 00:54:19,200 LIKE WE DID WITH EBOLA, AND 1307 00:54:19,200 --> 00:54:21,240 ASSESSING THE USEFULNESS AND 1308 00:54:21,240 --> 00:54:23,120 EPROTECTIVENESS OF THERAPEUTIC 1309 00:54:23,120 --> 00:54:24,760 AND PREVENTIVE INTERVENTION LIKE 1310 00:54:24,760 --> 00:54:25,720 WITH MALARIA. 1311 00:54:25,720 --> 00:54:29,680 IT'S NOT ONLY THOSE, YOU CAN USE 1312 00:54:29,680 --> 00:54:30,840 THESE AND SIMILAR MOLECULAR 1313 00:54:30,840 --> 00:54:33,400 TECHNIQUES AND MODALITIES TO 1314 00:54:33,400 --> 00:54:37,640 OTHER INFECTIOUS AGENTS, AND IN 1315 00:54:37,640 --> 00:54:41,840 THE FUTURE PATHOGEN-SPECIFIC 1316 00:54:41,840 --> 00:54:43,240 IMAGING MIGHT BE THE ANSWER IN 1317 00:54:43,240 --> 00:54:46,080 THE PERIPHERY AND IN THE BRAIN. 1318 00:54:46,080 --> 00:54:48,560 ED 1319 00:54:48,560 --> 00:54:51,080 WITH THAT I WOULD LIKE TO THANK 1320 00:54:51,080 --> 00:54:52,960 MY TEAM, DR. SHAH WHO HAS DONE A 1321 00:54:52,960 --> 00:54:56,360 LOT OF THE WORK, ALL THE 1322 00:54:56,360 --> 00:54:59,480 WONDERFUL FELLOWS WHO DO ALL THE 1323 00:54:59,480 --> 00:54:59,840 WORK. 1324 00:54:59,840 --> 00:55:04,400 I ALSO WANT TO THANK ALL OF OUR 1325 00:55:04,400 --> 00:55:05,040 COLLABORATORS AT NIH, IRF, 1326 00:55:05,040 --> 00:55:06,600 WITHOUT WHOM NONE OF THE EBOLA 1327 00:55:06,600 --> 00:55:10,000 WORK WOULD HAVE HAPPENED, ALSO 1328 00:55:10,000 --> 00:55:13,040 ALL MY MENTORS, OFFICIAL AND 1329 00:55:13,040 --> 00:55:15,640 UNOFFICIAL MENTORS, WHO HELPED 1330 00:55:15,640 --> 00:55:17,440 ME NAVIGATE NIH AND EVENTUALLY 1331 00:55:17,440 --> 00:55:20,160 GET TENURE AT NIH. 1332 00:55:20,160 --> 00:55:21,520 I'M REALLY THANKFUL. 1333 00:55:21,520 --> 00:55:27,720 I WANT TO THANK YOU FOR YOUR 1334 00:55:27,720 --> 00:55:30,080 TIME AND YOUR ATTENTION. 1335 00:55:30,080 --> 00:55:34,720 >> THANK YOU, DR. HAMMOUD. 1336 00:55:34,720 --> 00:55:36,760 YOU ILLUSTRATE IN YOUR RESEARCH 1337 00:55:36,760 --> 00:55:37,720 ADVANCES IN IMAGING INFECTIONS 1338 00:55:37,720 --> 00:55:39,640 ARE FAR BEYOND THE SIMPLE IMAGES 1339 00:55:39,640 --> 00:55:43,240 AND PICTURES THAT ARE OFFERING 1340 00:55:43,240 --> 00:55:44,040 INSIGHT INTO PHYSIOLOGY, 1341 00:55:44,040 --> 00:55:46,280 PATHOPHYSIOLOGY, AS YOU ALLUDE 1342 00:55:46,280 --> 00:55:48,680 TO PERHAPS EVEN 1343 00:55:48,680 --> 00:55:50,000 PATHOGEN-SPECIFIC IMAGING. 1344 00:55:50,000 --> 00:55:51,200 ONE QUESTION, A LOT OF 1345 00:55:51,200 --> 00:55:53,880 TECHNIQUES AND MODALITIES ARE 1346 00:55:53,880 --> 00:55:55,040 AVAILABLE IN RESEARCH-FOCUSED 1347 00:55:55,040 --> 00:55:55,400 ENVIRONMENTS. 1348 00:55:55,400 --> 00:55:57,000 DO YOU HAVE A THOUGHT AS TO 1349 00:55:57,000 --> 00:55:58,960 WHERE SOME OF THE MOLECULAR 1350 00:55:58,960 --> 00:55:59,840 IMAGING APPLICATIONS YOU'VE 1351 00:55:59,840 --> 00:56:02,280 REFERRED TO MAY BECOME MORE 1352 00:56:02,280 --> 00:56:05,160 BROADLY AVAILABLE IN CLINICAL 1353 00:56:05,160 --> 00:56:06,240 MEDICINE? 1354 00:56:06,240 --> 00:56:07,360 >> WELL, OUR HOPE IS THAT 1355 00:56:07,360 --> 00:56:09,440 EVERYTHING THAT WE DO IN THE 1356 00:56:09,440 --> 00:56:12,200 PRE-CLINICAL WORLD WILL ACTUALLY 1357 00:56:12,200 --> 00:56:15,160 BE TRANSLATED TO HUMAN 1358 00:56:15,160 --> 00:56:16,360 APPLICATIONS, AND PROBABLY IF WE 1359 00:56:16,360 --> 00:56:18,640 WANT TO SEE THE PROGRESSION FROM 1360 00:56:18,640 --> 00:56:19,520 PRE-CLINICAL TO CLINICAL, THE 1361 00:56:19,520 --> 00:56:24,240 BEST PLACE TO LOOK AT IS 1362 00:56:24,240 --> 00:56:24,480 ONCOLOGY. 1363 00:56:24,480 --> 00:56:26,280 ONCOLOGY HAS BEEN -- IT'S BEEN 1364 00:56:26,280 --> 00:56:27,640 MOVING AMAZINGLY. 1365 00:56:27,640 --> 00:56:29,480 ONE OF THE MOST RECENT ONES 1366 00:56:29,480 --> 00:56:31,400 ACTUALLY IS BEING ABLE TO 1367 00:56:31,400 --> 00:56:34,440 DIAGNOSE PROSTATE CANCER, FOR 1368 00:56:34,440 --> 00:56:35,040 EXAMPLE. 1369 00:56:35,040 --> 00:56:37,240 SO PSMA IS ONE OF THE LIGANDS 1370 00:56:37,240 --> 00:56:38,960 THAT HAS BEEN LABELED RECENTLY 1371 00:56:38,960 --> 00:56:41,520 AND THEY WERE FOUNDING TO MUCH, 1372 00:56:41,520 --> 00:56:43,920 MUCH BETTER THAN FDG-PET FOR 1373 00:56:43,920 --> 00:56:46,000 EXAMPLE FOR FOLLOWING UP 1374 00:56:46,000 --> 00:56:46,640 PROSTATE CANCER. 1375 00:56:46,640 --> 00:56:49,320 SO THAT WAS A SUCCESS STORY IN 1376 00:56:49,320 --> 00:56:52,720 ONCOLOGY WORLD, WHERE IT STARTED 1377 00:56:52,720 --> 00:56:54,040 IN ANIMALS, PRE-CLINICAL 1378 00:56:54,040 --> 00:56:56,000 MOLECULAR WORK, EVENTUALLY 1379 00:56:56,000 --> 00:56:57,640 BECAME CLINICALLY APPROVED. 1380 00:56:57,640 --> 00:57:01,080 ANOTHER ONE IS AMYLOID IMAGING, 1381 00:57:01,080 --> 00:57:01,240 CNS. 1382 00:57:01,240 --> 00:57:04,040 WHERE WE NOW CAN DIAGNOSES 1383 00:57:04,040 --> 00:57:05,000 ALZHEIMER'S DEMENTIA, WE DON'T 1384 00:57:05,000 --> 00:57:07,000 ONLY LOOK AT BRAIN VOLUME LOSS 1385 00:57:07,000 --> 00:57:08,760 OR FDG GOING DOWN BUT CAN SAY 1386 00:57:08,760 --> 00:57:10,360 FOR SURE IS THERE AMYLOID IN THE 1387 00:57:10,360 --> 00:57:12,200 BRAIN OR IS THERE NO AMYLOID? 1388 00:57:12,200 --> 00:57:13,840 SAME THING FOR TAU. 1389 00:57:13,840 --> 00:57:16,920 SO, I WOULD SAY INFECTION AND 1390 00:57:16,920 --> 00:57:17,760 INFLAMMATION IS PROBABLY -- 1391 00:57:17,760 --> 00:57:23,240 WE'RE LIKE AT THE END OF THAT 1392 00:57:23,240 --> 00:57:24,400 SPECTRUM. 1393 00:57:24,400 --> 00:57:26,200 EVERYTHING WE'RE DOING IS 1394 00:57:26,200 --> 00:57:27,960 THEORETICALLY MEANT TO IMPROVE 1395 00:57:27,960 --> 00:57:30,400 CLINICAL MEDICINE AND IMPROVE 1396 00:57:30,400 --> 00:57:31,880 THE DIAGNOSTIC ABILITIES OF 1397 00:57:31,880 --> 00:57:32,160 PATIENTS. 1398 00:57:32,160 --> 00:57:34,840 BUT WE'RE PROBABLY STILL A 1399 00:57:34,840 --> 00:57:37,360 LITTLE BIT FURTHER BACK, BUT THE 1400 00:57:37,360 --> 00:57:41,080 PROMISE IS THERE, AND I BELIEVE 1401 00:57:41,080 --> 00:57:44,560 THAT THE MORE PEOPLE DO 1402 00:57:44,560 --> 00:57:45,640 MOLECULAR IMAGING, AND MOLECULAR 1403 00:57:45,640 --> 00:57:46,680 IMAGING IS NOT ONLY PET, THERE 1404 00:57:46,680 --> 00:57:47,960 ARE OTHER THINGS. 1405 00:57:47,960 --> 00:57:54,280 THERE'S A LOT OF OPTICAL 1406 00:57:54,280 --> 00:57:55,720 IMAGING, ULTRASOUND, MR, MRS, 1407 00:57:55,720 --> 00:57:56,840 IRON OXIDE PARTICLES, SO THERE'S 1408 00:57:56,840 --> 00:57:59,520 A LOT OF STUFF THAT CAN BE DONE 1409 00:57:59,520 --> 00:58:01,600 TO IMPROVE THIS CONNECTION 1410 00:58:01,600 --> 00:58:02,240 BETWEEN PRE-CLINICAL AND 1411 00:58:02,240 --> 00:58:02,960 CLINICAL RESEARCH. 1412 00:58:02,960 --> 00:58:05,200 AND YES, IN TEN YEARS I WOULD 1413 00:58:05,200 --> 00:58:08,400 SAY A LOT OF THOSE THINGS WE'RE 1414 00:58:08,400 --> 00:58:09,880 NOW DOING MOLECULAR IMAGING 1415 00:58:09,880 --> 00:58:12,360 HOPEFULLY WILL BE IN PATIENTS. 1416 00:58:12,360 --> 00:58:15,480 >> THAT BRINGS US TO THE HOUR, 1417 00:58:15,480 --> 00:58:16,840 IT LOOKS LIKE. 1418 00:58:16,840 --> 00:58:19,440 THANK YOU FOR SHARING YOUR 1419 00:58:19,440 --> 00:58:21,000 CUTTING-EDGE RESEARCH, INSIGHTS 1420 00:58:21,000 --> 00:58:22,040 INTO THIS VERY EXCITING FIELD. 1421 00:58:22,040 --> 00:58:24,120 THANK YOU FOR JOINING US AND 1422 00:58:24,120 --> 00:58:24,880 TALKING. 1423 00:58:24,880 --> 00:58:27,240 AND TO EVERYONE ELSE, I WISH 1424 00:58:27,240 --> 00:58:28,080 EVERYONE A GOOD AFTERNOON. 1425 00:58:28,080 --> 00:58:28,840 THANK YOU ALL. 1426 00:58:28,840 --> 00:58:29,000 >> HAVE A GREAT DAY. 1427 00:58:29,000 --> 00:00:00,000 >> BYE-BYE.