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>OUR SPEAKER IS DR. DIMA
HAMMOUD, CENTER FOR INFECTIOUS
DISEASE IMAGING, NIH CLINICAL
CENTER, NATIONAL INSTITUTE OF
ALLERGY AND INFECTIOUS DISEASE.
DR. HAMMOUD EARNED HER MEDICAL
DEGREE AT AMERICAN UNIVERSITY IN
LEBANON, COMPLETED INTERNSHIP IN
INTERNAL MEDICINE, RESIDENCY IN
DIAGNOSTIC RADIOLOGY AT THE
AMERICAN UNIVERSITY.
IN 2001 SHE JOINED THE JOHNS
HOPKINS SCHOOL OF MEDICINE AS A
FELLOW IN RADIOLOGY, SECOND
FELLOWSHIP IN POSITRON IMAGING,
JOINED THE DEPARTMENT AT THE NIH
CLINICAL CENTER IN 2006, IN 2011
TENURE-TRACK INVESTIGATOR,
FOCUSING ON DEVELOPMENT OF
PRE-CLINICAL TRANSLATIONAL AND
CLINICAL MOW MOLECULAR IMAGING,
RELIABLE IMAGING BIOMARKERS OF
INFECTIOUS DISEASES, TO
UNDERSTAND PATHOPHYSIOLOGY SUCH
AS HIV, IN THE BRAIN AND
PERIPHERY, AS WELL AS
DEVELOPMENT AND VALIDATION OF
NOVEL FUNGAL INFECTIONS SPECIFIC
IMAGING BIOMARKERS IN ANIMAL
MODELS USING NON-INVASIVE
TECHNIQUES, MOSTLY PET IMAGING.
DR. HAMMOUD IS AN
INTERNATIONALLY AND NATIONALLY
RECOGNIZED EXPERT IN MOLECULAR
IMAGING, WORKS IN COLLABORATION
WITH NIAID'S BSL4 INTEGRATED
FACILITY AT FORT DETRICK.
SHE'S AUTHORED OVER 100
ARTICLES, NUMEROUS BOOK CHAPTERS
AND SERVESES CHAIR OF IMAGING
INFECTION INTEREST GROUP OF THE
WORLD MOLECULAR IMAGING SOCIETY.
SHE'S BOARD CERTIFIED IN
RADIOLOGY, ALSO STAFF
NEURORADIOLOGY IN RADIOLOGY
SCIENCE DEPARTMENT AT NIH
CLINICAL CENTER.
HER TALK TODAY IS ENTITLED THE
PROMISE OF MOW ELECTRIC IMAGING,
SPOTLIGHT ON CNS INFECTIONS.
PLEASE WELCOME OUR SPEAKER, DR.
HAMMOUD.
>> THANK YOU FOR THE NICE
INTRODUCTION AND FOR SHARING
YOUR LUNCH HOUR WITH ME TODAY.
OVER THE NEXT HOUR OR SO I'LL BE
TALKING ABOUT SOME OF THE WORK
WE'VE BEEN DOING CONCENTRATING
ON USING MOLECULAR IMAGING,
ADVANCED MR IMAGING TO TRY TO
BETTER UNDERSTAND CNS INFECTION
AND IMPROVE DIAGNOSTIC
ABILITIES.
I HAVE NO DISCLOSURES OR
CONFLICTS OF INTEREST.
SO, AS DR. BURKLOW SAID, I'M A
NEURORADIOLOGIST BY TRAINING.
WHENEVER A PATIENT PRESENTS WITH
A SUSPECTED CNS INFECTION WE
OBTAIN IMAGING, IMPORTANT IN
MANAGING THE INFECTIONS.
I USUALLY LOOK AT THOSE IMAGES
AND TRY TO NARROW DIFFERENTIAL
SPACE ON WHAT WE'RE SEEING, WE
LOOK FOR THE LOCATION OF THAT
ABNORMALITY, HOW MANY REGIONS
ARE THERE, SYNAPSES, SOLID MASS,
EDEMA?
AND ALONG WITH ALL THESE
COMBINATIONS OF FINDINGS ALONG
WITH THE CLINICAL PICTURE WE
USUALLY REACH A DIFFERENTIAL
DIAGNOSIS, EVERY NOW AND THEN WE
CAN TELL EXACTLY WHAT THE
DISEASE IS BUT IN MOST
SITUATIONS WE CAN'T TELL FOR
SURE WHAT'S GOING ON.
OR WE CANNOT DIAGNOSE FOR SURE
WHAT'S GOING ON.
THE OTHER ISSUE WITH
CONVENTIONAL IMAGING, SOMETIMES
YOU HAVE INFECTION, YOU'RE
FOLLOWING THE PATIENT DOING
IMAGING WITH MRI FOR EXAMPLE.
THE QUESTION IS, IS THE PATIENT
RECOVERING, IS THIS TISSUE?
SOMETIMES THE RESPONSE SIZE CAN
LAG BEHIND ACTUAL DISCOVERY.
THE THIRD PROBLEM MANY
INFECTIONS DON'T HAVE ANY MAJOR
ASSOCIATED ABNORMALITIES, YET
THE PATIENTS PRESENT WITH
NEUROLOGIC FINDINGS, AND THE
QUESTION IS HOW CAN WE ACTUALLY
DOCUMENT WHAT'S HAPPENING IN THE
BRAIN IF WE DON'T SEE ANYTHING
ON THE SURFACE?
AND THE ANSWER IS, YOU TRY TO
UNDERSTAND WHAT'S HAPPENING
UNDER THE SURFACE AND TRY TO
IDENTIFY MOLECULAR LEVEL
CHANGES, WHICH BRINGS US TO THE
TOPIC OF MOLECULAR IMAGING.
AND THIS IS A TERM THAT WAS
COINED APPROXIMATELY TWO DECADES
AGO TO ENCOMPASS A GROUP OF
MODALITIES WHICH SURPASS THE
CONVENTIONAL IMAGING TO MEASURE
BIOLOGICAL PROCESSES AT THE
CELLULAR AND SUBCELLULAR LEVEL
SO WE'RE NOT JUST LOOKING AT THE
STRUCTURE ANYMORE BUT AT THE
BIOLOGY OF WHAT'S HAPPENING IN
THE CELLS, WITHIN INTACT LIVING
SUBJECTS.
SO YOU COULD DO THAT WITH EX
VIVO AND IN VIVO, BUT WE CAN
STUDY BIOLOGICAL PROCESS IN
AUTHENTIC ENVIRONMENTS.
BUT THE ACTUAL DISCIPLINE OF
MOLECULAR IMAGING IS NOT A
STAND-ALONE SCIENCE.
IT DEPENDS HEAVILY ON MANY OTHER
DISCIPLINES AND FIELDS WITHOUT
WHICH IT COULD NOT GROW.
IT DEPENDS ON BASICS OF
MOLECULAR AND CELL BIOLOGY,
INFORMATICS, PHYSICS IS VERY
IMPORTANT.
ADVANCES IN NANOTECHNOLOGY,
GENETICS, CHEMISTRY, ALL THESE
CONSTITUTE THE BIG FIELD OF
MOLECULAR IMAGING.
HOWEVER, EVEN THOUGH THE TERM IS
NEW, THE CONCEPT IS NOT THAT
NEW.
IN FACT, IT'S ALWAYS BEEN QUOTE/
UNQUOTE MOLECULAR IMAGING.
FOR EXAMPLE, THIS IS A STUDY
DONE IN 1965, WHERE A
PHYSIOLOGIC CELLULAR PROCESS OF
IDENTIFICATION IN THE FOLLICULAR
CELL WAS CO-AUTHORED BY A SMART
SCIENTIST, USING IODINE 131
PRODUCED AN IMAGE OF THE THYROID
GRAND, THAT'S NOT A STRUCTURE,
THAT'S ACTUALLY THE FUNCTION OF
THE IMAGE THAT IS DEPICTED ON
THESE SCANS.
GRANTED THEY ARE NOT REALLY GOOD
LOOKING.
THIS IS LINEAR SCAN, PRECURSOR
OF THE PRECURSOR OF THE GAMMA
CAMERA, BUT AT THAT POINT WERE
ABLE TO ACHIEVE A FUNCTIONAL
IMAGE, AND THAT'S THE DEFINITION
OF MOLECULAR IMAGING.
SINCE THEN IT'S BECOME MORE
DIVERSE, THERE ARE MULTIPLE
MODALITIES INCLUDED UNDER THIS
BIG UMBRELLA.
WE ALSO HAVE SPECIFIC TYPES OF
MR, AS WELL OPTICAL IMAGING,
BIOLUMINESCENCE, PHOTOACOUSTIC
ULTRASOUND TECHNIQUES, COMPUTED
TOMOGRAPHY, BUT TODAY I'LL FOCUS
ON PET IMAGING, POSITRON
EMISSION TOMOGRAPHY.
YOU'RE FAMILIAR WITH PET,
ESSENTIALLY TALKING ABOUT A
RADIOACTIVE ISOTOPE, DECAYS BY
PRODUCTION OF POSITRON,
COLLIDES, ANNIHILATION, DETECTED
BY OPPOSING CONSTRUCTS.
MOST ARE RINGS SET ON THE
PATIENT, THE MORE RINGS THE
BIGGER THE FIELD OF VIEW YOU
HAVE.
THIS INFORMATION ABOUT WHERE THE
ANNIHILATION OCCURS AND HOW MUCH
OCCURS IS THEN TRANSLATED
RECONSTRUCTED AND YOU END UP
WITH AN IMAGE THAT YOU CAN LOOK
AT, QUANTIFY, AND DIAGNOSE
DISEASES BASED ON IT.
AND THINGS HAVE REALLY
PROGRESSED, IF YOU LOOK AT THE
FIRST FDG-PET SCAN IN 1986, YOU
IT TELL WE'VE GOTTEN FURTHER
THANKS TO TECHNOLOGICAL ADVANCES
MAKING MACHINES AND IMPROVING
BIOENGINEERING.
THAT'S WHAT MAKES PET IMAGING
ONE OF THE HIGHEST SENSITIVITY
TECHNIQUES IN MOLECULAR IMAGING
WITH PICOMOLAR CONCENTRATIONS DE
DETECTED BY PET.
HUMAN SCANNERS ARE 45-MILLIMETER
RESOLUTION, WHICH IS REALLY VERY
BAD IF YOU COMPARE TO MRI FOR
EXAMPLE BUT THESE ARE IMPROVING
WITH ALL THE NEW ADVANCEMENTS
WITH NEW SCANNERS, ALSO EVEN
RADIATION EXPOSURE ASSOCIATED
WITH PET IS BECOMING LESS AND
LESS.
AND THIS IS VERY IMPORTANT, FOR
EXAMPLE, FOR PEDIATRIC IMAGING.
ALL THIS MAKES PET IMAGING A
VERY ATTRACTIVE MODALITY TO
DIAGNOSE DISEASES AND TO PERFORM
MOLECULAR IMAGING.
AND THAT BRINGS US TO FDG, WHICH
IS THE MOST FAMOUS AND MOST
CLINICALLY USED MOLECULAR
IMAGING PROBE EVER.
AND FDG IS VERY WELL KNOWN, USED
IN CANCER IMAGING.
IT'S A HYDROPHILIC MOLECULE,
NEEDS TO BE TRANSPORTED, DOES
NOT CROSS THE BRAIN.
TRANSPORTERS, WE HAVE A LARGE
NUMBER OF THOSE THAT ARE
IDENTIFIED BUT GLUT1 IS
EXPRESSED ON MOST MAMMALIAN
CELLS, IT HAPPENS TO NOT
DIFFERENTIATE BETWEEN FDG AND
GLUCOSE, YOU END UP WITH THIS
MOLECULE, GOES INSIDE THE CELL,
PHOSPHORYLATED, BECOMES CHARGED,
DOES NOT LEAVE THE CELL, YOU END
UP WITH A MAP OF GLUCOSE
METABOLISM.
THAT'S THE BASIS FOR USING IT IN
CANCER IMAGING WHERE IT'S MADE A
HUGE IMPACT ON DIAGNOSIS AND
MANAGEMENT OF PATIENTS.
BUT IT'S NOT ONLY IN CANCER THAT
IT'S IMPORTANT.
IT'S ALSO IMPORTANT IN INFECTION
AND INFLAMMATION BECAUSE WE KNOW
ACTIVATED IMMUNE CELLS
UPREGULATE TO GLUT-1 LEVELS,
BECOMING MORE AND MORE FDG-AVID,
THIS IS A STUDY AT NIAID, HER
PATIENTS, SOME DEVELOPED WHAT WE
REFER TO AS IRIS, AND WHERE YOU
GET ACTIVATION OF IMMUNE CELLS
AS A RESULT OF TREATING
PATIENTS.
YOU CAN SEE HERE THAT AFTER
TREATMENT, GLUT-1 EXPRESSION
INCREASED IN THESE MONOCYTES,
THE BASIS FOR IMAGING INFECTION
INFLAMMATION IN THOSE PATIENTS.
WHICH BRINGS US TO THE BRAIN,
WHERE THINGS ARE A LITTLE BIT
MORE COMPLICATED, BECAUSE IN THE
BRAIN, IT'S NOT ONLY THESE
IMMUNE CELLS THAT WE'RE TALKING
ABOUT, BUT WE ALSO HAVE NEURONS.
NEURONS ONLY USE GLUCOSE FOR
THEIR ENERGY SUPPLIES, SO
GLUCOSE -- NEURONS TAKE A LOT OF
FDG.
EVERYBODY ASSUMES ALL THE FDG
UPTAKE OR MOST IN THE BRAIN IS
ACTUALLY IN NEURONS, BUT
NOWADAYS THERE ARE QUESTIONS
ABOUT THE FACT THAT GLIAL CELLS
AND INCLUDING MICROGLIA AND
ASTROCYTES, THAT THEY ARE
ACTUALLY MORE AND MORE
RESPONSIBLE FOR FDG UPTAKE, IN
THE BIOESSENCE STATE, IN ALL
CASES WHAT WE'RE REALLY LOOKING
AT ESSENTIALLY IS TWO EVENTS.
THE FIRST ONE IS IF YOU HAVE
INFLAMMATION, ACTIVATION OF
IMMUNE CELLS, THERE'S INCREASED
GLUT-1, INCREASED USE OF
GLUCOSE, INCREASED FDG UPTAKE.
IF YOU'RE LOSING NEURONS LIKE
HAPPENS WITH ALZHEIMER'S, FOR
EXAMPLE, THEN YOU HAVE DECREASED
FDG UPTAKE.
BEING ABLE TO DECIPHER WHAT'S
HAPPENING IS NOT ALWAYS EASY BUT
CAN YOU DONE IF YOU DESIGN YOUR
STUDIES APPROPRIATELY.
AND IF YOU DO LONGITUDINAL
IMAGING, FOR EXAMPLE.
IN THE CLINIC, THIS INCREASED
FDG UPTAKE ASSOCIATED WITH
INFLAMMATION IS WHAT WE USE TO
ANSWER QUESTIONS.
ONE COMMON QUESTION IN HIV
POSITIVE PATIENTS, FOR EXAMPLE,
IS DIFFERENTIATING THE ETIOLOGY
OF ENHANCING LESIONS OF THE
BRAIN, SO PATIENTS WITH HIV
PRESENT, THE QUESTION IS, IS
THIS TUBERCULOSIS?
THERE'S A LOT OF LITERATURE
ABOUT USING FDG UPTAKE VALUES,
SPECIFICALLY SUV-MAX.
AND IF YOU FIND THE SUV-MAX
VALUES ARE THE LOW RANGE, YOU
THINK MORE ALONG THE LINES OF
TOXOPLASMOSIS, IN THE HIGH RANGE
LYMPHOMA, AND TUBERCULOSIS FALLS
IN BETWEEN.
IT'S VERY IMPORTANT TO KNOW
THESE ARE JUST GUIDELINES,
SUV-MAX VALUES VARY DEPENDING ON
THE SCANNER YOU'RE USING,
RECONSTRUCTION METHOD, ET
CETERA.
SO THESE ARE GUIDELINES.
OFTEN WE CAN GIVE AN ANSWER OF
THE MOST LIKELY POSSIBILITY OF
WHAT THE LESION IS.
AN IMPORTANT THING IN THE CLINIC
THOUGH IS TO KNOW THAT
IMMUNOCOMPROMISED PATIENTS WHO
DON'T MOUNT STRONG IMMUNE
REACTION UPTAKE WITH FDG IS
LOWER.
FOR EXAMPLE, THIS IS A VERY UGLY
LOOKING ASPERGILLOMA, IT CAN BE
VERY HELPFUL, DIFFERENTIATING
FROM TUMOR, FOR EXAMPLE.
THIS IS A VERY INTERESTING CASE,
A PATIENT WITH CNS LYMPHOMA,
AFTER TREATMENT THE PATIENT
COMES BACK WITH A HYPER
METABOLIC COMPONENT, WHICH TURNS
OUT TO BE THE CANCER.
THEN YOU HAVE A LESS METABOLIC
COMPONENT, THAT TURNED OUT TO BE
AN ASPERGILLOMA.
THIS DIFFERENTIAL UPTAKE BETWEEN
INFECTION AND TUMOR CAN BE
HELPFUL IN DIAGNOSING WHAT'S
HAPPENING IN THE BRAIN OF THOSE
PATIENTS.
THE OTHER USE OF FDG PET THAT WE
HAVE HERE AT NIH IS IN
COLLABORATION WITH DOCTORS
LEONAKIS AND WILLIAMSON,
PATIENTS WITH FUNGAL INFECTIONS.
THE PROBLEM IS THAT EVEN WHEN
YOU TREAT THEM, YOU ALMOST
ALWAYS END UP WITH A CERTAIN
AMOUNT OF ENHANCEMENT ON MRI,
AND THE QUESTION IS IS THERE
STILL AN INFECTIOUS PROCESS
GOING ON?
WE'VE BEEN USING PET IMAGING TO
FOLLOW THOSE PATIENTS AND SEE IF
WE CAN DETECT A DECREASE IN FDG
PET UPTAKE THAT INDICATES
RESPONSE TO TREATMENT.
IT DOESN'T MEAN THAT THE FUNGUS
IS GONE, ONLY THEY ARE
RESPONDING TO TREATMENT.
AS LONG AS YOU CAN CONTROL THEM
WITHOUT THIS FDG UPTAKE COMING
BACK, THEN YOU'RE IN GOOD SHAPE.
THIS IS ANOTHER EXAMPLE OF CNS,
A PATIENT WITH ENHANCEMENT,
THICKENING IN THE DISTAL CORD,
ON FDG PET WE SAW EXTENSIVE
AMOUNT OF FDG UPTAKE CONSISTENT
WITH INFLAMMATORY PROCESS THAT'S
HAPPENING.
ON FOLLOW-UP HOWEVER THE FDG
UPTAKE AFTER TREATMENT GOES DOWN
QUITE A BIT, FASTER THAN THE
CHANGES WE'RE SEEING ON MRI.
WHEN RESOLVED STILL HAVE
ENHANCEMENT ON MRI.
FDG BECOMES COMPLEMENTARY TO
CONVENTIONAL IMAGING.
AND A CLINICAL EXAMPLE I'M GOING
TO SHOW, AGAIN POINTING OUT TO
THE FACT FDG MIGHT NOT DETECT
WHEN THE IMMUNE SYSTEM IS NOT
WELL BUT IF YOU HAVE IMMUNE
RECOVERY, LIKE IN IRIS PATIENTS,
YOU MIGHT BE ABLE TO DETECT
CHANGES EASILY.
THIS IS A PATIENT WITH PML IRIS,
DR. SERETI'S PATIENT, HE
PRESENTED WITH ABNORMAL
ENHANCEMENT AFTER TREATMENT,
INCREASED FDG UPTAKE, PROBABLY
ON THE CD 8 POSITIVE T CELLS
THAT HAVE CONTRIBUTED TO THIS
IMMUNE RECOVERY, AND FDG UPTAKE.
EVENTUALLY THIS UPTAKE GOES AWAY
SUGGESTING OR CONSISTENT WITH
RESPONSE TO TREATMENT.
BUT AS I SAID EARLIER IT'S NOT
ONLY IN THE CLINIC THAT PET
IMAGING AND FDG PET IS VERY
IMPORTANT.
IN FACT, IN THE RESEARCH THESE
MODALITIES CAN BE VERY IMPORTANT
TO BETTER UNDERSTAND WHAT'S
HAPPENING IN CNS INFECTIONS
BECAUSE OFTEN THE CNS INFECTIONS
CAN HAVE POORLY UNDERSTAND PAT
-- PATHOPHYSIOLOGY, WE CAN
UNDERSTAND WHAT'S HAPPENING,
MITIGATING OR CONTRIBUTING
FACTORS TO DAMAGE IN THE BRAIN.
YOU CAN USE THEM TO ASSESS THE
LONG TERM SEQUELAE OF CNS
INFECTIONS, EVALUATE EFFICACY OF
TREATMENT.
I'M GOING TO GIVE EXAMPLES OF
ALL OF THESE.
A HAVE GOOD EXAMPLE IS NEUROHIV,
MULTI-FACTORIAL, HIV POSITIVE
PATIENTS IN THE EARLY DAYS OF
THE EPIDEMIC USED TO HAVE SEVERE
DISEASE AND END UP IN DEMENTIA.
MORE RECENTLY THOUGH AFTER MAJOR
ADVANCES IN THERAPY, PATIENTS
ARE SURVIVING MUCH LONGER,
NEUROCOGNITIVE FUNCTION NOT AS
SIGNIFICANT BUT STILL EXISTS,
IT'S A REAL PROBLEM AND AFFECTS
THE QUALITY OF LIFE.
THE QUESTION IS, WHAT IS
HAPPENING IN THE BRAIN OF THOSE
PATIENTS, SO THEY ARE OPTIMALLY
TREATED.
THE ASSUMPTION OF OF
NEUROINFLAMMATION WITH
PRODUCTION OF CHEMOKINES,
VARIETY OF OTHER COMPOUNDS, WE
KNOW GP 120 ARE NEUROTOXIC,
ASTROCYTIC LOST, INCREASED
PRODUCTION COULD BE
CONTRIBUTING, EFFECT OF
ANTIRETROVIRAL THERAPY,
SOMETHING NOW WE'RE THINKING
MORE ABOUT, THAT'S COMORBIDITIES
OF CARDIOVASCULAR DISEASE.
WITH USE OF MOLECULAR IMAGING
AND THE ABILITY TO ACTUALLY
SELECT TECHNOLOGIES ONE CAN
PARSE OUT CONTRIBUTION OF THESE
DIFFERENT FACTORS, AND TO THE
END RESULT OF NEURONAL INJURY,
AND HOPEFULLY PROPOSE
IMPROVEMENT TO THE WAY WE'RE
MANAGING THOSE PATIENTS.
NEURO-HIV THERE ARE MULTIPLE
TARGETS, PERHAPS THE EASIEST IS
GLUCOSE METABOLISM WHICH AS I
SAID EARLIER IS USUALLY A
COMBINATION OF NEUROINFLAMMATION
AS WELL AS NEURONAL FUNCTION OR
DYSFUNCTION.
WE USED FDG PET TO EVALUATE
PATIENTS A.R.T. NAIVE, ADVANCED
HIV INFECTION WITH VERY LOW CD 4
COUNTS, IMAGE THEM WITH FDG AT
BASELINE.
THEN WE IMAGE THEM AFTER THEY
WERE TREATED.
WITHIN WEEKS FROM THEIR
TREATMENT.
AND IN ALL HONESTY WE DIDN'T
EXPECT TO SEE A LOT OF CHANGE IN
A FEW WEEKS.
BUT WE FOUND SIGNIFICANT DROP IN
FDG UPTAKE AND THE BASAL
GANGLIA, CAUDATE, HYPOTHALAMUS,
WHICH CORRELATED POSITIVELY WITH
A DROP IN INTERLEUKIN 6 OR SCD
14 INFLAMMATORY MARKERS
SUGGESTING THERE HAS BEEN OR WAS
INFLAMMATORY PROCESS HAPPENING
AT THIS LEVEL WHICH AFTER
CONTROL OF THE VIRAL INFECTION,
AFTER CONTROL OF THE
INFLAMMATION, THE AMOUNT OF
UPTAKE DECREASED.
WE SAW THE CORTEX STARTED
ACTUALLY SHOWING MORE FDG
UPTAKE, SPECIFICALLY IN THE
FRONTAL LOBE, WHERE THE CHANGES
WERE STATISTICALLY SIGNIFICANT.
AND, AGAIN, THAT CORRELATED
POSITIVELY ACTUALLY CORRELATED
NEGATIVELY WITH IMPROVEMENT OF
NEUROINFLAMMATION.
SO THERE SEEMS TO BE A
REVERSIBLE CORTICAL DYSFUNCTION
OCCURRING IN THE STAGE, ONCE YOU
DECREASE INFLAMMATION, DECREASE
VIRAL REPLICATION YOU HAVE
RECOVERY OF SOME FUNCTION
SUGGESTING IT'S IMPORTANT TO
START TREATMENT VERY EARLY ON.
SUBSET OF THOSE PATIENTS CAME
BACK TWO YEARS LATER, AT THAT
POINT WE FOUND THAT THE UPTAKE,
FDG UPTAKE IN THE BASAL GANGLIA
WAS EVEN LOWER.
AND WHEN WE COMPARED THEM TO
NORMAL CONTROLS, THE UPTAKE WAS
ACTUALLY LOWER THAN NORMAL
CONTROLS.
SO THAT ABNORMALLY LOW.
AND AT THIS POINT THE ONLY
CONCLUSION IS THAT THERE HAS
BEEN NEURONAL LOSS HAPPENING IN
THE BASAL GANGLIA, AND THAT'S
NOT UNUSUAL CONSIDERING THESE
ARE THE AREAS THAT WE'RE MOST
NEURAL INFLAMMATION.
THAT, AGAIN, TAKES US BACK TO
WHAT WE REFER TO AS THE LEGACY
FACT, A CERTAIN AMOUNT OF
NEUROCOGNITIVE DYSFUNCTION OR
NEURONAL LOSS THAT HAPPENS IN
EARLY STAGE OF HIV INFECTION
ASSOCIATED WITH RESIDUAL
NEUROCOGNITIVE DEFICIT THAT'S
NOT GOING TO IMPROVE WITH
ANTIRETROVIRAL TREATMENT, SO
EARLIER TREATMENT CAN BETTER SO
DAMAGE CAN BE ALLEVIATED.
WE LOOKED AT PATIENTS, FROM THE
ALL HANDS PROTOCOL.
THEY HAD BEEN INFECTED FOR MUCH
LONGER PERIODS OF TIME AND
TREATED, APPROXIMATELY 20 YEARS.
WE WANTED TO SEE WHAT HAPPENS
WAY BEYOND TWO YEARS OF
FOLLOW-UP WE HAD.
IN THIS GROUP OF PATIENTS, THERE
WERE TWO MAJOR FINDINGS.
FIRST, WE NOTICED , WE COMPARED
TO HEALTHY CONTROLS AND CONTROLS
WITH COMORBIDITIES AND FOUND
THAT DOING A VARIABLE SELECTION
MODEL, METABOLISM WAS PREDICTED
BY HIV STATUS SUGGESTING DIRECT
HIV EFFECT.
PERSISTENT OR RESIDUAL DESPITE
THE FACT THOSE PATIENTS ARE
OPTIMALLY TREATED.
WHAT WAS EVEN MORE INTERESTING
IS THAT WHEN WE LOOKED AT THE
WHOLE BRAIN METABOLISM, IT
WASN'T HIV THAT WAS THE CULPRIT
ANYMORE.
IN FACT, IN THOSE PATIENTS, IT
WAS CARDIOVASCULAR DISEASE THAT
WAS ASSOCIATED WITH THE WORST
HYPO METABOLISM, AND WHEN WE DID
THE STATISTICAL ANALYSIS, THE
WHOLE BRAIN METABOLISM PREDICTED
BY CARDIOVASCULAR DISEASE, NOT
HIV STATUS.
IT'S IMPORTANT AS PHYSICIANS
TAKING CARE OF HIV-POSITIVE
PATIENTS IT'S IMPORTANT TO KNOW
IT'S NOT ENOUGH TO TREAT THE
INFECTION.
ONE HAS TO BE VERY AGGRESSIVE,
TARGETING CARDIOVASCULAR
DISEASE, IF YOU WANT TO STOP
NEUROCOGNITIVE DYSFUNCTION FROM
HAPPENING OR WORSENING.
THERE ARE ALSO OTHER WAYS OF
LOOKING AT THE BRAIN,
NEUROINFLAMMATION IN THE BRAIN.
IN FACT A MORE SPECIFIC WAY OF
LOOKING AT THAT, THAT IS
TARGETING MARKERS THAT ARE
EXPRESSED IN IMMUNE CELLS AND
ACTIVATED IN IMMUNE CELLS.
PERHAPS THE MOST FAMOUS TARGET
IS WHAT WE REFER TO AS
TRANSLOCATOR PROTEIN, A MEMBRANE
RECEPTOR, THAT IS EXPRESSED IN A
LOT OF IMMUNE CELLS BUT IN THE
BRAIN IT'S EXPRESSED IN
MICROGLIA, AND IN MONOCYTE
DERIVED MACROPHAGES AND OTHER
CELL TYPES.
YOU CAN SEE HERE THE STAINING
LOCALIZES WITH MICROGLIAL AND
ASTROCYTIC MARKERS.
THE GOOD THING IS THAT IN NORMAL
BRAIN, THE LEVEL OF EXPRESSION
OF TSPO IS LOVE.
IS LOW.
IF THERE'S ANY KIND OF INJURY
YOU GET UPREGULATED EXPRESSION
OF TSPO, AND THAT'S REFLECTION
OF NEUROINFLAMMATIONS.
IF YOU CAN MEASURE TSPO, YOU CAN
MEASURE INFLAMMATION IN THE
BRAIN.
WE HAD ONE LIGAND FOR THE
LONGEST PERIOD OF TIME, FOR TSPO
IMAGING, BUT THAT HAD
NON-SPECIFIC BINDING, IT DIDN'T
HAVE VERY GOOD BIOAVAILABILITY.
SO PEOPLE STARTED OR A GROUP
STARTED WORKING ON SECOND
GENERATION TSPO LIGANDS.
ONE OF THE FIRST SECOND
GENERATION LIGANDS WAS DEVELOPED
AT NIH BY DR. ENNIS AND DR.
PIKE, AND IT WAS A GREAT LIGAND
AND ACTUALLY LED TO MORE AND
MORE DISCOVERY ABOUT TSPO.
WHICH I'M NOT GOING TO GO INTO
DETAILS OF.
BUT TSPO IS ONE OF THE MOST
AVAILABLE AND BEST TARGETS, SO
WE WANTED TO BETTER UNDERSTAND
WHAT'S HAPPENING IN THE BRAINS
OF HIV-INFECTED PATIENTS IN THE
EARLY STAGES OF DISEASE.
BUT BECAUSE WE CANNOT IMAGE
PATIENTS BEFORE THEY ARE
INFECTED WE DECIDED TO USE AN
ANIMAL MODEL OF INFECTION, AND
THAT IS SIV-INFECTED MONKEY.
THIS WAS A COLLABORATION WITH
DR. VANESSA HIRSCH, DR. DEMASS
YO AND DR. NATH, INFECTED, AND
USE A LIGAND, WE HAD TO GET
CREATIVE WITH BOLUS METHODS,
RECORD ACTIVITY VALUES IN
DIFFERENT LOCATIONS IN THE BRAIN
OVER TIME.
SO WE PERFORMED THIS
EQUILIBRIUM -- THIS METHOD TO
ESTABLISH EQUILIBRIUM AND
DISPLACE, AND THIS WAY YOU CAN
SEPARATE THE SPECIFIC FROM
NON-SPECIFIC BINDING.
SO WE IMAGING ANIMALS AT
BASELINE, AT FOLLOW-UP, WE HAD
EXPECTED TO SEE THAT AFTER THEY
WERE INOCULATED AND THEY HAD A
LOT OF CSF VIRAL LOAD IN THE
BRAIN AND CSF EXPECTED TO SEE A
LOT OF NEUROINFLAMMATION.
INSTEAD WE SAW A DROP, THIS IS
POST INOCULATION, ACTUALLY THE
TOTAL UPTAKE OR TOTAL
DISTRIBUTION VOLUME IS ACTUALLY
LOWER.
SO INSTEAD OF NEUROINFLAMMATION
WHAT WE WERE SEEING WAS ACTUALLY
MICROGLIAL LOSS AND NO
MICROGLIAL ACTIVATION.
THEN WE TREATED ANIMALS AND SAW
AS WE TREATED ANIMALS AND VIRAL
LOAD GOES DOWN, THIS BINDING
STARTED GOING UP.
AND THEN THE SAME THING HAPPENS
AFTER WE STOPPED TREATMENT.
AGAIN, HAPPENING, THIS ANIMAL,
WE DROPPED THE VIRAL LOAD HAVE
INFLAMMATION, INCREASE, IT GOES
DOWN.
THE ANIMAL EUTHANIZED AT HIGH
VIRAL LOAD, TIME POINT SHOWS
MUCH LESS BINDING IN THE
BASELINE, THIS ANIMAL WHERE THE
VIRAL LOAD WAS MODERATELY
ELEVATED YOU SEE THERE'S QUITE A
BIT OF BINDING SUGGESTING
NEUROINFLAMMATION.
SO WE CONCLUDED IN THE EARLY
STAGES OF DISEASE WHEN CSF VIRAL
LOADS ARE HIGH MICROGLIAL
INFLAMMATION IS CONVERSELY
CORRELATED.
IMMUNOFLUORESCENCE WAS DONE WITH
DR. MERRICK AT NINDS.
WHEN YOU HAVE VERY HIGH CSF
VIRAL LOAD, THESE MACROPHAGE
STAINS, POOR STAINING OF THESE
CELLS AND A LOT OF APOPTOTIC
MARKERS.
WHEN THE CSL VIRAL LOAD IS
MODERATELY ELEVATED THERE'S
ACTUAL INFLAMMATION, NOT AS MUCH
APOPTOSIS.
THAT CONFIRMED THE FINDINGS THAT
IN THE EARLY STAGES WHEN
PATIENTS HAVE HIGH CSF VIRAL
LOAD IT'S POSSIBLE THERE ISN'T
AS MUCH NEURAL INFLAMMATION AS
MICROGLIAL LOSS, CONSISTENT WITH
SOME WORK WHICH SUGGESTED THAT
MITOCHONDRIA AND ASTROCYTES WHEN
INFECTED, A LOT OF THEM DIED AND
FIVING CELLS BECOME RESERVOIRS.
THIS IS APOPTOSIS.
BUT MORE INTERESTINGLY WE FOUND
THAT NEURONS WERE ALSO DYING.
SO THIS IS A NEURON WITH
APOPTOTIC MARKERS, AND THIS IS
NOT GOING TO COME BACK.
AND, AGAIN, THAT TAKES US BACK
TO EARLY FINDING, NEURONAL LOSS
IN THE BRAIN, AND THAT PROBABLY
ACCOUNTS FOR THIS IRREVERSIBLE
NEURONAL INJURY THAT HAPPENS
AFTER INFECTION AND BEFORE
ANTIRETROVIRAL THERAPY AND DOES
NOT REVERSE.
AGAIN TREATING PATIENTS AS EARLY
AS POSSIBLE IS THE ONLY WAY TO
PREVENT THIS IRREVERSIBLE
DAMAGING FROM HAPPENING.
ANOTHER INTEREST OF OURS WAS
ACTUALLY IMAGING
NEUROTRANSMITTER SYSTEMS.
AND, FOR EXAMPLE, IT'S ALWAYS
BEEN KNOWN DOPE DOPAMINERGIC
SYSTEM IS SUSCEPTIBLE TO HIV, IN
EARLY DAYS OF THE EPIDEMIC
PATIENTS WERE PRESENTING WITH
THIS.
WE WANTED TO SEE HOW THIS IS
RELATED TO VIRAL PROTEIN
NEUROTOXICITY.
SO, WE HAD AN ANIMAL MODEL, HIV
TRANSGENIC RAT, WHICH WE KNEW
HAD A VIRAL PROTEIN EXPRESSION,
AND WE WANTED TO IMAGE THAT
ANIMAL OVER TIME.
HOWEVER, WHEN YOU DEAL WITH
RODENTS, YOU CANNOT REALLY USE A
PET SCANNER BECAUSE PET SCANNERS
HAVE VERY -- WELL, RESOLUTION IS
NOT THAT GREAT.
IT'S 4 TO 5 MILLIMETERS, PERFECT
FOR HUMANS BUT NOT GOOD ENOUGH
FOR SMALL ANIMALS, 4 TO 5
MILLIMETERS IS NOT GOING TO CUT
IT LOOKING FOR A SMALL LESION IN
THE BRAIN OF A RAT, FOR EXAMPLE.
SO, FOR THIS WE USED WHAT WE
REFER TO AS A SMALL ANIMAL
PET-CT SCANNER, THIS WAS
ACTUALLY DEVELOPED HERE AT NIH.
DEPARTMENT OF NUCLEAR MEDICINE.
COURTESY OF MIKE GREEN.
AND IT WAS CALLED ATLAS, SMALL
ANIMAL PET SCANNER, THIS WAS AN
AMAZING INVENTION.
WHICH OTHER TIME, IMPROVEMENT
AND ADVANCED TECHNOLOGY, WITH
DEVELOPMENT OF MUCH SMALLER
DETECTORS, FOR EXAMPLE, AND
LARGER TUBES, WE ENDED UP WITH
MACHINES LIKE THE ONE WE HAVE
HERE AT NIH.
THIS IS OUR MICRO PET-CT SCANNER
WITH HIGHER PHOTON SENSITIVITY,
BETTER ENERGY RESOLUTION,
COINCIDENCE TIME RESOLUTION IS
MUCH BETTER, HAVE BETTER
PERFORMANCE, AND EVENTUALLY
SPATIAL RESOLUTION IS MUCH
BETTER.
FOR THIS MACHINE, FOR EXAMPLE,
IT'S SUPPOSED TO BE .8
MILLIMETERS, IN THE CENTER OF
THE FIELD OF VIEW WHICH IS WAY
BETTER THAN IF YOU COMPARE TO A
BIG PET SCANNER.
AND EVEN WHERE YOU DON'T ACHIEVE
THAT, IT'S STILL IN THE 1
MILLIMETER RANGE, WHICH IS VERY
APPROPRIATE FOR USE IN SMALL
ANIMALS.
SO WE USE THE MICRO PET-CT
SCANNER TO LOOK AT THE SMALL
ANIMAL MODEL OF HIV INFECTION, A
NON-INFECTIOUS MODEL, TRANSGENIC
RAT, EXPRESSION OF VIRAL
PROTEINS.
IN FACT WE HAD TESTED THIS
ANIMAL OVER LONG PERIOD OF TIME,
WE FOUND THAT VIRAL PROTEINS
SPECIFICALLY GP 120 WAS
EXPRESSED IN THE SERUM AND
BRAIN.
WE WERE IMAGING WITH MRI AND WE
NOTICED THEY WERE LOSING VOLUME
OVER TIME, SPECIFICALLY IN THE
BASAL GANGLIA.
SO WE DECIDED TO LOOK AT THE
SPECIFIC STATUS OF THE
DOPAMINERGIC SYSTEM USING PET
SCANNER.
WE USED WHO LIGANDS, FIRST IS
TARGETED AGAINST THE DOPAMINE
TRANSPORTER, PRESYNAPTIC
ASSESSMENT OF THE DOPAMINERGIC
SYSTEM, CORONAL PET SCANS
OVERLAID ON CORONAL MR IMAGES.
YOU CAN SEE THE TRANSGENIC MOUSE
HAS LESS BINDING THAN THE
CONTROL MOUSE.
AND THEN WE USED ANOTHER LIGAND,
F-18-FALLYPRIDE, DECREASE
BINDING COMPARED TO CONTROL
ANIMALS SUGGESTING THIS IS PRE
AND POST SYNAPTIC DOPAMINERGIC
DYSFUNCTION HAPPENING IN THOSE
ANIMALS, LIKELY AS A RESULT OF
EXPOSURE TO VIRAL PROTEINS.
SPECIFICALLY THAT ANIMALS WITH
HIGHER 120 LEVELS WITH ARE THE
ONES THAT SHOWED LOWEST DOPAMINE
TRANSPORTER AND D2/D3 RECEPTOR
DENSITY.
HIV VIRAL PROTEINS ARE
NEUROTOXICS TO DOPAMINERGIC
NEURONS, SHOWING THERE'S LESS
DOPAMINE TRANSPORTER, TYROSINE
HIGH HYDROXYLASE.
IT WAS MOSTLY IN THE OLDER
ANIMALS.
AND WHY IS THIS IMPORTANT?
BECAUSE VIRUS IN THE BRAIN IS
ACTUALLY -- THERE ARE THEORIES
THERE'S STILL PRODUCTION OF
VIRAL PROTEINS EVEN THOUGH THE
PATIENTS ARE TREATED.
DR. AVI NATH AT NINDS HAS SHOWN
THAT THERE'S EXPRESSION IN THE
CSF OF TREATED HIV-POSITIVE
PATIENTS, LIKELY EVEN IF WE'RE
TREATING THOSE PATIENTS THERE
ARE STILL VIRAL PROTEINS, AND
THAT COULD CAUSE WORSENING OF
THE DOPAMINERGIC PATHOLOGY IN
THOSE PATIENTS.
SO, WE TOOK THIS WORK WE DID ON
THE RATS, TRANSLATED IT TO A
HUMAN STUDY, SUPPORTED BY OFFICE
OF AIDS RESEARCH, WE JUST
WRAPPED UP THE IMAGING AND ARE
STARTING ANALYSIS LOOKING AT
DOPAMINERGIC AND SERATONERGIC,
COMPARED TO CONTROLS, SO WE CAN
TELL FOR SURE NOW THAT IF THERE
IS RESIDUAL DOPAMINERGIC AND
SERATONERGIC DYSFUNCTION OR IF
THERE ISN'T.
SHIFTING GEARS, ANOTHER SET OF
DISEASES WHERE MOW WILL --
MOLECULAR IMAGING IS HELPFUL IS
IN EBOLA FOR EXAMPLE, IN
UNDERDEVELOPED COUNTRIES WITH
LIMITED RESOURCE, DIFFICULT TO
STUDY THEM WHERE THEY OCCUR,
BECAUSE OF THOSE REASONS.
EBOLA, IN THE MIDST OF THE
EPIDEMIC, NOBODY WAS THINKING
LOUDLY ABOUT HOW IT'S AFFECTING
THE BRAIN BECAUSE PATIENTS WERE
DYING OF OTHER REASONS.
BUT THEN AFTER THE EPIDEMIC WAS
UNDER CONTROL, PATIENTS STARTED
COMPLAINING OF WHAT THEY
REFERRED TO AS POST-EBOLAVIRUS
DISEASE SYNDROME, AND THIS IS A
COMPILATION OF SYMPTOMS
INCLUDING FATIGUE, DIFFICULTY
SLEEPING, HEADACHES, ISSUES WITH
MEMORY, WITH MOOD, AS WELL AS
OTHER VISUAL AND AUDITORY
PROBLEMS.
THE QUESTION IS, WHAT EXACTLY IS
HAPPENING?
NOBODY THOUGHT EBOLA COULD
ACTUALLY HAVE DIRECT CNS
EFFECTS.
TO BETTER UNDERSTAND, WE
COLLABORATED WITH INTEGRATIVE
RESEARCH FACILITY, A BSF 4
FACILITY IN FORT DETRICK,
STATE-OF-THE-ART IMAGING
CAPABILITIES.
SO WE COLLABORATED WITH TO IMAGE
RHESUS MACAQUES WITH EBOLA
VIRUS, TO EVALUATE ANIMALS
LONGITUDINALLY, IMAGED AT
BASELINE BEFORE INOCULATIONED,
AND AFTER INOCULATION, 18F-FDG
PET AND MRI WITH T1 MAPPING, TO
SEE IF THERE'S LOSS OF BRAIN
BARRIER INTEGRITY.
WITH FDG PET WHAT WE SAW WAS
EVIDENCE OF INCREASED FDG UPTAKE
IN CERTAIN LOCATIONS IN THE
BRAIN, MOSTLY BRAINSTEM AND
THALAMUS, OVER TIME
SIGNIFICANTLY INCREASED OVER
TIME.
THE REGIONS WHICH WERE MOST
INVOLVED WITH THALAMUS,
MID-BRAIN, PONS.
THAT WAS INTERESTING,
CORRELATIONS WITH VIRAL OR WITH
CYTOKINE LEVELS, BOTH PRO- AND
ANTI-INFLAMMATORY CYTOKINES.
FOR EXAMPLE, THE PONS WAS THE
PART OF THE BRAIN WHICH WAS
MOSTLY INVOLVED, IT WAS ACTUALLY
ALSO THE FINDINGS WERE
CORRELATED WITH PLASMA VIRAL
LOAD AND INTERLEUKIN 10,
ASSUMING INFLAMMATORY PROCESS
THAT COULD ACCOUNT FOR THIS
INCREASED ACTIVITY AND INDEED
WERE ABLE TO SHOW EARLY
INFLAMMATION IN BRAINS OF THOSE
ANIMALS.
SO AGAIN THIS IS THE
COLLABORATION WITH DR. NATH, YOU
CAN SEE THE CELLS ARE STARTING
TO GET LARGER, PROCESSES ARE
SHORTER.
PROBABLY BECAUSE ANIMALS DID NOT
SURVIVE LONG ENOUGH FOR THAT TO
DEVELOP.
THIS IS PROBABLY ONE OF THE
REASONS WE'RE SEEING THIS
INCREASED UPTAKE.
WE ALSO LOOKED MORE CAREFULLY
AND WE NOTICED THERE WAS --
THERE WERE GROUPS OF NEURONS
SPECIFICALLY IN THE SAME
LOCATIONS, BRAINSTEM AND
THALAMI, STAINING FOR THE EBOLA
VIRUS ANTIGEN, VP-40.
THIS IS THE NEURONAL MARKER.
A LOT WERE APOPTOTIC WHEN
STAINED.
SO BUT WHAT WAS INTERESTING, WE
ASSUMED THEY ARE BEING INFECTED,
PROBABLY UNDERGOING APOPTOSIS,
BUT WHAT WAS REALLY INTERESTING
IS THAT THEY WERE ALSO
UPREGULATING GLUCOSE
TRANSPORTERS.
LOOK AT CELLS INVOLVED, THERE'S
INCREASED GLUT-3 STAINING IN
THOSE CELLS COMPARED TO CELLS
NOT INVOLVED.
WHICH COULD BE THAT THERE'S AN
INCREASE IN GLUCOSE AND FDG
UPTAKE IN THIS STATE OF
APOPTOSIS THAT COULD BE
ACCOUNTING PARTIALLY AT LEAST
FOR THAT FDG UPTAKE THAT WE SAW
IN THE ANIMALS.
THE SECOND PART OF THE
EXPERIMENT WAS LOOKING AT THE
WAY THE BRAIN IS BEHAVING AFTER
INOCULATION, USING T1 MAPPING.
SO FIRST WE DID MR IMAGING,
THERE WEREN'T REALLY ANY MAJOR
ABNORMALITIES WE COULD DETECT.
DECIDED TO PURSUE T1 MAPPING,
YOU CAN ACTUALLY DETECT CONTRAST
IN THE BRAIN AND YOU CAN DETECT
THE CONSISTENCY, TISSUE
CONSISTENCY WITHIN EACH VOXEL.
THE REASON IS T1 RELAXATION
VALUES DIVERSITY BETWEEN
DIFFERENT COMPONENTS IN THE
BRAIN, FOR EXAMPLE, AT 3 TESLA
FLUID HAS LONG RELAXATION TIME.
IF YOU HAVE A VOXEL WHICH HAS
MORE FLUID IN IT, T1 VALUES GO
UP.
WE GAVE CONTRAST, WANTED TO LOOK
AT THE PARAMAGNETIC EFFECTS OF
GADOLINIUM, IF YOU HAVE CONTRAST
THAT'S LEAKING ACROSS THE
BLOOD-BRAIN BARRIER YOU SEND UP
WITH MORE GADOLINIUM, MORE T1
SHORTENING, DROP IN
POST-CONTRAST VALUES WILL ARE
MORE INTENSE.
WE USE THE TWO APPROACHES TO
IMAGE THE ANIMALS AT BASELINE,
AS WELL AS AFTER INOCULATION.
AND WE FOUND THAT THERE WAS
ACTUALLY EVIDENCE OF EDEMA IN
THE BRAIN.
IT'S REALLY SUBTLE, BECAUSE T1
VALUES WERE INCREASING.
AND IN THE TWO REGIONS,
STATISTICALLY SIGNIFICANT.
IF YOU LOOK AT THE MAPS YOU CAN
SEE THE T1 VALUES ARE INCREASING
A LITTLE BIT IN CERTAIN
LOCATIONS.
SUGGESTING THERE'S MORE FLUID IN
THE BRAIN.
AND WHEN WE GAVE CONTRAST, WE
HAD FURTHER EXACERBATION OF DROP
IN T1 VALUES SUGGESTING THERE'S
BEEN LEAKAGE OF CONTRAST INTO
THE EXTRACELLULAR SPACE AS WELL.
ALL OF THESE VALUES CORRELATED
WITH VIREMIA AND CYTOKINES.
IF YOU HAVE A LOT OF
INFLAMMATION IN THE PERIPHERY
AND IN THE BRAIN, THAT ACTUALLY
IS ONE OF THE CONTRIBUTORS TO
BLOOD-BRAIN BARRIER DYSFUNCTION
ALONG WITH THE FACT THAT EBOLA
VIRUS INFECTS ENDOTHELIAL CELLS.
SO, OBVIOUSLY WE HAD TO GO BACK
TO DRAGON AND LABELED -- WE
STAINED THE BRAINS OF THE
ANIMALS TO SEE IF THERE'S
LEAKAGE OF ALBUMIN, THAT'S WHAT
WE FOUND.
THESE AREAS OF -- GREEN AREAS
ARE AREAS OF ALBUMIN
ACCUMULATION IN THE BRAIN, THE
PROTEIN IS NOT SUPPOSED TO CROSS
INTACT BLOOD-BRAIN BARRIER.
IF IT DOES, IT INDICATES THAT
THERE IS A DISRUPTION.
ALBUMIN IS NEURO TOXIC, AS WELL
AS MANY OTHER POTENTIAL
MOLECULES THAT HAVE CROSSED THE
BLOOD-BRAIN BARRIER AT THAT
POINT AND COULD HAVE CAUSED
NEURONAL LOSS.
SOME NEURONS WE FOUND TO BE
APOPTOTIC STAINED GREEN,
SUGGESTING THAT THEY WERE
ACTUALLY TAKING ALBUMIN IN.
SO, WE THINK THAT THIS ALONG
WITH NEUROINFLAMMATORY CHANGES
COULD BE -- COULD ACCOUNT AT
LEAST PARTIALLY FOR THE
NEUROLOGIC SYMPTOMS WE'RE SEEING
IN SURVIVORS.
SPECIFICALLY THAT A LOT OF
SYMPTOMS OF THE SURVIVORS
CORRELATE WITH OR ARE ACTUALLY
CORRESPONDING TO DEFICITS IN THE
BRAINSTEM AND THE SUBCORTICAL
STRUCTURES.
THE QUESTION IS WHETHER OTHER
VIRAL INFECTIONS LIKE COVID FOR
EXAMPLE COULD ACTUALLY BE
ASSOCIATED WITH SIMILAR PROCESS.
THERE HAS BEEN A LOT OF WORK ON
COVID AND TRYING TO UNDERSTAND
WHAT'S HAPPENING IN THE BRAIN OF
SURVIVORS INFECTED, NICE REVIEW
RECENTLY BY DR. NATH ABOUT
POTENTIAL CAUSES OF CNS ISSUES
IN COVID PATIENTS BUT AT LEAST
IN ONE STUDY THERE WAS EVIDENCE
OF LEAKAGE OF PROTEINS IN THE
BRAIN OF THOSE PATIENTS.
SO WHETHER THIS CONTRIBUTES TO
THEIR SYMPTOMS OR NOT, IT'S
STILL REALLY NOT ANSWERED.
STILL NEED TO DO MORE WORK TO
FIGURE THAT ONE OUT.
SO, THE LAST EXAMPLE I'M GOING
TO GIVE IS HOW YOU COULD USE
ADVANCED MR IMAGING TO ASSESS
TREATMENT EFFECT, WORK IN
COLLABORATION WITH DR. PIERCE
AND DR. MILLER, AT NIAID,
CEREBRAL MALARIA IS A DISEASE
THAT OCCURS IN CHILDREN A LOT,
MOSTLY LESS THAN 5 YEARS OLD.
UNFORTUNATELY, IT'S ASSOCIATED
WITH SEVERE MORBIDITY AND
MORTALITY.
AND IT'S OBVIOUSLY AN ENDEMIC
AREAS, WITH NOT A LOT OF
RESOURCES, THE PATHOPHYSIOLOGY
OF DISEASE IS NOT VERY WELL
UNDERSTOOD BUT WE DO KNOW FOR
SURE THERE'S EDEMA, IT'S NOT
LIKE EBOLA WHERE IT'S VERY MILD.
IN THESE PATIENTS EDEMA, THEY
GET BRAIN SWELLING, HERNIATE AND
DIE.
THE PROPOSED CAUSE IS GLUTAMATE
EXCITEOTOXICITY.
THE REASON WE STARTED THIS
PROJECT, THERE WAS A NEW
ADJUVANT THERAPY, PROPOSED TO
REVERSE DISEASE MANIFESTATIONS
IN INFECTED MOUSE MODELS.
INFECTED MOUSE MODELS USED FOR
MALARIA IS EXPERIMENTAL CM, CAN
WE USE MRI WITH QUANTIFICATION
TO ASSESS DISEASE PROGRESSION
AND RESPONSE TO TREATMENT WITH
GLUTAMINE ANTAGONISTS, THAT'S
EXACTLY WHAT WE DID.
WE STARTED BY IMAGING INFECTED
ANIMALS, CORONAL IMAGES, WE
PERFORMED THIS WORK AT THE MOUSE
IMAGING FACILITY, USED 9.4 TESLA
SCANNER.
YOU CAN SEE THERE EDEMA IN THE
OLFACTORY BULBS, IN THE STERNAL
CAPSULES, WHICH WE WERE ABLE TO
QUANTIFY AND ALSO MEASURED ADC
VALUES, DIFFUSION IMAGING, THESE
INDICATE WHETHER THERE'S EDEMA,
INCREASE IN ADC VALUES
SUGGESTING THIS IS FHASOGENIC.
THERE WAS LEAKAGE OF CONTRAST IN
CORPUS CALLOSUM AND EXTERNAL CAP
SUPERVISORS.
WE DOCUMENTED BLOOD-BRAIN
BARRIER DYSFUNCTION, IMAGING
LONGITUDINALLY BEFORE AND AFTER
TREATMENT, THAT'S ONE OF THE
GREATEST THINGS ABOUT MOLECULAR
IMAGING, CAN YOU DO LONGITUDINAL
IMAGING.
EACH ANIMAL WILL BE ITS OWN
CONTROL.
SO, WE ALLOWED THE ANIMALS TO
PROGRESS TO BECOME SICK, AND
THEN WE TREATED THEM AND IMAGING
THEM AGAIN.
AND AS YOU CAN SEE HERE THIS IS
DAY 12 POST-TREATMENT, WERE ABLE
TO SHOW RESOLUTION OF EDEMA AND
PHOTOACCUMULATION IN THE BRAIN
AND MEASURED THIS
QUANTITATIVELY, AGAIN RELAXED
MEASURING TISSUE CONSISTENCY,
RESOLUTION OF CONTRAST SEEN
BEFORE TREATMENT.
CAN WE VISUALIZE AND QUANTIFY?
THE ANSWER IS YES.
THIS IS ANOTHER PROTEIN THAT'S
NOT SUPPOSED TO BE IN THE BRAIN
PARENCHYMA, WE SAW SOME AREAS OF
HEM ACKNOWLEDGE -- HEMORRHAGE IN
THOSE ANIMALS.
CONCLUSION, USING THE MODEL WITH
SIMILAR CHARACTERISTICS TO HUMAN
DISEASE, WE KNOW THERE'S EDEMA,
IN THE ANIMAL THERE'S EDEEMA WE
REVERSED WITH ANTAGONISTS, THIS
COULD POTENTIALLY BE USED TO
TREAT CEREBRAL MALARIA IN
TREATMENT, POST CLINICAL
TRANSLATION.
THAT HASN'T HAPPENED YET BUT
IT'S SOMETHING THAT IS
SUPPORTIVE OF THE POTENTIAL OF
USING THESE DRUGS FOR SUCH A
HORRIFIC DISEASE.
SO, WHAT'S THE FUTURE?
THERE'S MUCH MORE TO MOLECULAR
IMAGING THAN TRYING TO
UNDERSTAND PATHOPHYSIOLOGY AND
IMAGE TREATMENT EFFECT.
PERHAPS THE HOLY GRAIL IS TO GET
TO A POINT WHERE WE HAVE LIGANDS
THAT CAN TELL US EXACTLY WHAT
THE PATHOGEN IS, THAT'S WHAT
REREFER TO AS PATHOGEN-SPECIFIC
IMAGING.
THIS MOLECULAR IMAGING FIELD IS
GROWING A LOT.
LAST TEN YEARS WAY MORE PEOPLE
INTERESTED IN DEVELOPING LIGANDS
THAT TARGET SPECIFIC PATHOGENS.
PERHAPS THE MOST FAMOUS ONE IS
F-18 FLUORO DEOXY SORBITOL,
FOUND TO BE A GOOD LIGAND FOR
GRAM NEGATIVE BACTERIA,
ENTEROBACKTERALIS.
WE COLLABORATED AND DEVELOPED
ANIMAL MODELS OF ASPERGILLUS AND
BACTERIAL INFECTION, FDS IS A
GOOD LIGAND FOR
ENTEROBACKTERALIS.
THERE ARE MANY OTHER LIGANDS
THAT ARE BEING DEVELOPED, MOST
OF WHICH ARE ACTUALLY DEVELOPED
FOR BACTERIAL INFECTIONS.
BY DIFFERENT GROUPS, STANFORD, U
PENN, UCSF, DIFFERENT PLACES.
WE ARE -- MY LAB, WE'RE
INTERESTED IN FUNGAL INFECTION,
AND THAT'S WHY WE'VE DEVELOPED
ALL THESE FUNGAL INFECTION
MODELS INCLUDING IV INFECTION,
DEVELOPING CNS,
ASPERGILLOMAOSIS, WE HAVE TWO
APPROACHES TO USING THIS, FIRST
WE'RE USING SUBSTRATE SIMILAR TO
THE WAY SORBITOL WAS FOUND TO BE
GOOD FOR GRAM NEGATIVE BACTERIA,
WE'RE TRYING TO FIND SUBSTRATES
PREFERRED BY FUNGI, AND LABEL
THOSE SUBSTRATES, MOSTLY SUGARS,
AND INJECT THEM IN OUR ANIMAL
MODELS AND SEE IF WE CAN HAVE
SPECIFIC UPTAKE BY FUNGI.
AND EVENTUALLY IF WE FIND ONE OF
THOSE WE HAVE QUITE A FEW
CONTENDERS, THOSE COULD
POTENTIALLY BE TRANSLATED TO
HUMAN USE AND BECAUSE THEY ARE
SUGARS THEY ARE MORE OR LESS
EASILY TRANSLATED.
THE OTHER APPROACH WE'RE DOING
IS BY TARGETING CELL WALL
COMPONENTS OF FUNGI.
WE KNOW THEY ARE PRESENT IN THE
WALL AND NOT IN MAMMALIAN CELLS,
IF WE TARGET WITH ANTIBODIES OR
ANTIBODY FRAGMENTS OR
NANOBODIES, WE MIGHT BE ABLE TO
ACTUALLY DIAGNOSE
ASPERGILLUSOSIS IN VIVO.
WE'RE IN THE EARLY STAGES OF
TESTING MULTIPLE LIGANDS, WE
HAVE SOME EARLY SUCCESSES, AND
WE'RE HOPING THAT ONCE WE
VALIDATE LIGANDS IN THE
PRIVILEGE WHICH WE CAN GO TO THE
BRAIN.
THE BRAIN IS A LITTLE BIT MORE
TRICKY BECAUSE WHEN YOU HAVE
INFECTION AND YOU HAVE
BLOOD-BRAIN BARRIER OBSTRUCTION
YOU HAVE TO MAKE SURE WHAT
YOU'RE LOOKING AT IS NOT
LEAKAGE.
THIS IS LEAKAGE ACROSS THE
BLOOD-BRAIN BARRIER SO WE HAVE
TO DO SPECIAL STUDIES TO MAKE
SURE WE SPECIFIC UPTAKE.
SO IN CONCLUSION, MOLECULAR
IMAGING CAN BE VERY INSTRUMENTAL
IN EVALUATION OF CNS INFECTIONS,
ONCOLOGY WORLD HAS DISCOVERED
THIS MUCH EARLIER THAN WE DID.
THERE'S A LOT OF CANCER RESEARCH
HAPPENING WITH MOLECULAR
IMAGING, NOT AS MUCH WITH
INFLAMMATION AND INFECTION.
BUT AS I SAID, YOU CAN USE THOSE
TECHNIQUES TO BETTER UNDERSTAND
DISEASE PATHOPHYSIOLOGY, AS I
SHOWED WITH HIV, ASSESSING
LONG-TERM SEQUELAE OF INFECTION
LIKE WE DID WITH EBOLA, AND
ASSESSING THE USEFULNESS AND
EPROTECTIVENESS OF THERAPEUTIC
AND PREVENTIVE INTERVENTION LIKE
WITH MALARIA.
IT'S NOT ONLY THOSE, YOU CAN USE
THESE AND SIMILAR MOLECULAR
TECHNIQUES AND MODALITIES TO
OTHER INFECTIOUS AGENTS, AND IN
THE FUTURE PATHOGEN-SPECIFIC
IMAGING MIGHT BE THE ANSWER IN
THE PERIPHERY AND IN THE BRAIN.
ED
WITH THAT I WOULD LIKE TO THANK
MY TEAM, DR. SHAH WHO HAS DONE A
LOT OF THE WORK, ALL THE
WONDERFUL FELLOWS WHO DO ALL THE
WORK.
I ALSO WANT TO THANK ALL OF OUR
COLLABORATORS AT NIH, IRF,
WITHOUT WHOM NONE OF THE EBOLA
WORK WOULD HAVE HAPPENED, ALSO
ALL MY MENTORS, OFFICIAL AND
UNOFFICIAL MENTORS, WHO HELPED
ME NAVIGATE NIH AND EVENTUALLY
GET TENURE AT NIH.
I'M REALLY THANKFUL.
I WANT TO THANK YOU FOR YOUR
TIME AND YOUR ATTENTION.
>> THANK YOU, DR. HAMMOUD.
YOU ILLUSTRATE IN YOUR RESEARCH
ADVANCES IN IMAGING INFECTIONS
ARE FAR BEYOND THE SIMPLE IMAGES
AND PICTURES THAT ARE OFFERING
INSIGHT INTO PHYSIOLOGY,
PATHOPHYSIOLOGY, AS YOU ALLUDE
TO PERHAPS EVEN
PATHOGEN-SPECIFIC IMAGING.
ONE QUESTION, A LOT OF
TECHNIQUES AND MODALITIES ARE
AVAILABLE IN RESEARCH-FOCUSED
ENVIRONMENTS.
DO YOU HAVE A THOUGHT AS TO
WHERE SOME OF THE MOLECULAR
IMAGING APPLICATIONS YOU'VE
REFERRED TO MAY BECOME MORE
BROADLY AVAILABLE IN CLINICAL
MEDICINE?
>> WELL, OUR HOPE IS THAT
EVERYTHING THAT WE DO IN THE
PRE-CLINICAL WORLD WILL ACTUALLY
BE TRANSLATED TO HUMAN
APPLICATIONS, AND PROBABLY IF WE
WANT TO SEE THE PROGRESSION FROM
PRE-CLINICAL TO CLINICAL, THE
BEST PLACE TO LOOK AT IS
ONCOLOGY.
ONCOLOGY HAS BEEN -- IT'S BEEN
MOVING AMAZINGLY.
ONE OF THE MOST RECENT ONES
ACTUALLY IS BEING ABLE TO
DIAGNOSE PROSTATE CANCER, FOR
EXAMPLE.
SO PSMA IS ONE OF THE LIGANDS
THAT HAS BEEN LABELED RECENTLY
AND THEY WERE FOUNDING TO MUCH,
MUCH BETTER THAN FDG-PET FOR
EXAMPLE FOR FOLLOWING UP
PROSTATE CANCER.
SO THAT WAS A SUCCESS STORY IN
ONCOLOGY WORLD, WHERE IT STARTED
IN ANIMALS, PRE-CLINICAL
MOLECULAR WORK, EVENTUALLY
BECAME CLINICALLY APPROVED.
ANOTHER ONE IS AMYLOID IMAGING,
CNS.
WHERE WE NOW CAN DIAGNOSES
ALZHEIMER'S DEMENTIA, WE DON'T
ONLY LOOK AT BRAIN VOLUME LOSS
OR FDG GOING DOWN BUT CAN SAY
FOR SURE IS THERE AMYLOID IN THE
BRAIN OR IS THERE NO AMYLOID?
SAME THING FOR TAU.
SO, I WOULD SAY INFECTION AND
INFLAMMATION IS PROBABLY --
WE'RE LIKE AT THE END OF THAT
SPECTRUM.
EVERYTHING WE'RE DOING IS
THEORETICALLY MEANT TO IMPROVE
CLINICAL MEDICINE AND IMPROVE
THE DIAGNOSTIC ABILITIES OF
PATIENTS.
BUT WE'RE PROBABLY STILL A
LITTLE BIT FURTHER BACK, BUT THE
PROMISE IS THERE, AND I BELIEVE
THAT THE MORE PEOPLE DO
MOLECULAR IMAGING, AND MOLECULAR
IMAGING IS NOT ONLY PET, THERE
ARE OTHER THINGS.
THERE'S A LOT OF OPTICAL
IMAGING, ULTRASOUND, MR, MRS,
IRON OXIDE PARTICLES, SO THERE'S
A LOT OF STUFF THAT CAN BE DONE
TO IMPROVE THIS CONNECTION
BETWEEN PRE-CLINICAL AND
CLINICAL RESEARCH.
AND YES, IN TEN YEARS I WOULD
SAY A LOT OF THOSE THINGS WE'RE
NOW DOING MOLECULAR IMAGING
HOPEFULLY WILL BE IN PATIENTS.
>> THAT BRINGS US TO THE HOUR,
IT LOOKS LIKE.
THANK YOU FOR SHARING YOUR
CUTTING-EDGE RESEARCH, INSIGHTS
INTO THIS VERY EXCITING FIELD.
THANK YOU FOR JOINING US AND
TALKING.
AND TO EVERYONE ELSE, I WISH
EVERYONE A GOOD AFTERNOON.
THANK YOU ALL.
>> HAVE A GREAT DAY.
>> BYE-BYE.