ronald boellaard [email protected]
DESCRIPTION
Molecular Imaging using Positron Emission Tomography: Assessment of (neuro-)receptor changes with PET. Ronald Boellaard [email protected]. Even voorstellen (mini CV). Ronald Boellaard Huidige functie: klinisch fysicus en UHD bij de afdeling Nucleaire Geneeskunde, VUmc, A’dam - PowerPoint PPT PresentationTRANSCRIPT
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Molecular Imaging using Positron Emission Tomography:
Assessment of (neuro-)receptor changes with PET
Ronald [email protected]
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Even voorstellen (mini CV)• Ronald Boellaard• Huidige functie: klinisch fysicus en UHD bij de afdeling
Nucleaire Geneeskunde, VUmc, A’dam
• Vooropleiding:- VWO (Gym-β), 1987- Exp.Natuurkunde (en Biologie), 1994- AIO/promovendus op het NKI (afdeling RT) , 1998- opleiding klin.fys. Op VUmc, 2001- klin.fys./UHD op VUmc – tot heden
• Klinische of Medische Fysica = toegepaste fysica
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Presentation• General introduction NM and PET• Physics and principles of PET
- general introduction- overview of (neuro-receptor) tracers- positron emission and coincidence detection
• PET pharmacokinetic analysis- principles of kinetic modelling- generation of parametric images
• SPM example of assessment of (neuro-) receptor change
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EmissionTomography
Physiology Imaging
Biochemistry Quantification
Pharmacokinetics Flexibility
NM & Positron Emission Tomography
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The spectrum of medical imaging Jones, 1996
Structure/anatomy X-ray/CT/MRI
Physiology US, SPECT, PET, MRI/S
Metabolism PET, MRS
Drug distribution PET
Molecular pathways PET
Molecular targets PET, SPECT
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Clinical Applications Clinical Applications • Oncology
• Cardiology
• Neurology / Psychiatry
• Pneumology
• Nephrology
......
• Oncology
• Cardiology
• Neurology / Psychiatry
• Pneumology
• Nephrology
......
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Very basic principle of nuclear medicine and PET
• Inject radiopharmaceutical (single photon or positron emitter labelled to a drug)
• Use gamma or PET camera to:- evaluate distribution of radiopharmaceutical at some time after injection
- evaluatie uptake, retention and washout of radiopharmaceutical = dynamic or kinetic information
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I. Qualitative analysis of PET studies“qualitative/visual inspection”
Examples of FDG whole body scans
Purpose: staging, unknown primary
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II. Semi-quantitative analysis of PET studies“standard uptake values (SUV)”
SUV is the uptake of a radiopharmaceutical, normalised to the injected doseand body weight (or lean body mass or body surface area etc)
regions of interest analysis: Average uptake (Bq/cc) in e.g. tumor
Purpose: diagnosis (benign/malignant), prognosis, response monitoring, definition of RT treatment volumes,…
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CTI / Siemens HR+ PET scanner RDS 111 15O-cyclotron
Department of Nuclear Medicine and PET Research
location ‘hospital’
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Department of Nuclear Medicine and PET Research
location ‘Radionuclide Centre’
HRRT PET scannerGMP lab with 6 hot cells
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The High Resolution Research Tomograph (HRRT) PET scanner
HRRTCPS Research
• 8 panel detector heads
• 60.000 LSO crystals
• 1 crystal = 2.1 x 2.1 x 7.5 mm
• 1 billion lines of response
• Cs-137 singles transmission
• 3D only, no septa
• Only 10 scanners in the world (up to now 4 operational)
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[11C]-Verapamil for imaging Pgp (Blood Brain Barrier Research)
mdr1a(-/-)/1b(-/-) KO mouse
mdr1a+/+/1b(+/+)WT mouse
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Figure A: HR+, 7 mm resolution
Figure B: HRRT, 2.5 mm resolution
Figure A: HR+, 7 mm resolution
Figure B: HRRT, 2.5 mm resolution
0.0
5000.0
10000.0
15000.0
20000.0
25000.0
30000.0
[Bq/
cc]
0.0
5000.0
10000.0
15000.0
20000.0
25000.0
30000.0
[Bq/
cc]
Figure A: HR+, 7 mm resolution
Figure B: HRRT, 2.5 mm resolution
HRRT upcoming protocols: Clinical Comparison with HR+:
A STUDY IN NORMAL SUBJECTS USING THE TRACERS [11C]RACLOPRIDE, [11C]FLUMAZENIL AND [18F]FP-b-CIT.
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HRRT upcoming protocols: Clinical Comparison with HR+:
A STUDY IN NORMAL SUBJECTS USING THE TRACERS [11C]RACLOPRIDE, [11C]FLUMAZENIL AND [18F]FP-b-CIT.
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Isotope production
Nuclear reactions t1/2
18F (p,n) 110 min
11C (p,a) 20 min
13N (p,a) 10 min
15O (p,n) 2 min
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GMP- LAB
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Current Tracers [11C][11C]Flumazenil
central type benzodiazepine receptor
(R)-[11C]PK11195 activated microglia
[11C]Raclopride D2/D3
(R) -[11C]Verapamil PgP in BBB
[11C]R116301 NK1 receptor
[11C] PIB amyloid
A B
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Current Tracers [18F]
[18F]FP-CITdopamine transporter
[18F]MPPF5HT1a receptor
[18F]FDDNPamyloid
[18F]FLTproliferation
[18F]Prolineaminoacid
[18F]FDG glucose metabolism
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Current Tracers[15O]
[15O]H2Operfusion
[15O]O2 oxygen consumption
[15O]CO blood volume
OXYGEN EXTRACTION FRACTION
CBF CMRO OEFCBF CMRO OEF
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Presentation• General introduction NM and PET• Physics and principles of PET
- principles- overview of (neuro-receptor) tracers- positron emission and coincidence detection
• PET pharmacokinetic analysis- principles of kinetic modelling- generation of parametric images
• SPM example of assessment of (neuro-) receptor change
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Positron emission
511 keV fotonen
positron annihilates with electron
Annihilation produces 2 photons of 511 keV which are sent out in opposite directions
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Positron emission detection
Positron emission tomography is based on the simultaneous (coincidence) detection of both annihilation photons
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PET
radio-nuclide: positron emitter -> 2 photons
acquisition: coincidence-detection
coincidence processor
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PET image reconstruction
ProjectionsProjections
ImageImage
ReconstructionReconstruction
PET scanner acquires projection
reconstruction of activity distribution in patient
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PET Image reconstruction
FilteredBackprojection
IterativeReconstruction
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Results patients (2)Example images, early frame, poor statistics, ‘fully converged’
FBP NAW-OSEM WLS-nn SP-OS-(W)LS
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Presentation• General introduction NM and PET• Physics and principles of PET
- principles- overview of (neuro-receptor) tracers- positron emission and coincidence detection
• PET pharmacokinetic analysis- principles of kinetic modelling- generation of parametric images
• SPM example of assessment of (neuro-) receptor change
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Tracer Kinetic Modelling
Tracer Model:
Purpose:
Method:
Mathematical description of thefate of the tracer in the humanbody, in particular in the organunder study
To quantify functional entitiesgiven the distribution ofRadioactivity (over time)
Divide possible distribution oftracer in a limited number ofdiscrete compartments
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Brain
FDG uptake as function of time
T=0
T=60min
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pharmacokinetic modelling
Dynamic scanParametric image representingbinding of tracer in tissue
Purpose: generation of image representing distribution of PET pharmacokinetic parameter: glucose consumption, DNA synthesis, perfusion etc etc.
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Uptake, retention and washout of radiopharmaceutical
• Used radiopharm. (=tracer)
• Supply of tracer in arterial blood (= input function)
• “Physiology” of tumor/organ, which can be quantified using a PET-pharmacokinetic model
Shape and amplitude of time activity curve depends on:
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Dynamic PET scanspharmacokinetic analysis
• dynamic scans consist of 20 to 40 sequential acquisitions during a 60 min period
• dynamic scans provide info on the variation of the activity(=pharmaceutical) in an organ/tumor as function of time
• dyn. scans are made to study and quantify the “functional or physiological” behaviour of the organ of interest (glucose and oxygen consumption, blood flow, blood volume, neuroreceptor density)
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PET scan
Bolus injector
Bolustoediening bij dyn. (Ex) scans
Loodpot met activiteit
Veneuze inspuiting
Bloodsampler
detectorpompwaste
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Analysis of dynamic PET scansInput function
0
50
100
150
200
250
0 2 4 6 8 10
Tijd (min)
Blo
od
ac
tiv
ity
(k
Bq
/cc
) 1022 keV
511 keV
manual samples
Input function also needs to be corrected for metabolites and plasma/blood ratio’s
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Blood FreeBound
(or metabolizedor trapped)
Example of Two Tissue Compartment Model
Tissue
PET
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Analyse van dynamische PET scanskinetische analyse
0.0E+00
1.0E+04
2.0E+04
3.0E+04
4.0E+04
0 20 40 60 80Tijd (min)
Ac
t.co
nc.
(Bq
/cc
)
0
50
100
150
200
250
0 2 4 6 8 10
Tijd (min)
Blo
od
ac
tiv
ity
(k
Bq
/cc) 1022 keV
511 keV
manual samples
K1
k2
k3
k4Cf CbCa
Quantitative value of apharmacokineticparameter, such as:-glucose comsumption-Perfusion-DNA synthesis-Hypoxia
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Overview of ‘common’ pharmacokinetic models
Plasma input models
• Single tissue compartment model (1TC-R)
• Single tissue compartment model (1TC-Ir)
• Irreversible two tissue compartment model (2TC-Ir)
• Reversible two tissue compartment model (2TC-R)
Reference tissue input models
• Simplified reference tissue model
• Full reference tissue model
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Reversible single tissue compartment model with plasma input
Blood
Tissue
PET
K1
k2
K1=E x F, E=extraction and F=flow=perfusionVd= K1/k2 = volume of distribution
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Irreversible single tissue compartment model with plasma input
Blood
Tissue
PET
K1
K1=E x F, E=extraction and F=flow=perfusion
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Irreversible two tissue compartment model with plasma input
k3Blood
Tissue
PET
K1
k2
K1=E x F, E=extraction and F=flow=perfusionKi= K1 x k3/(k2+k3)
FreeBound/
metabolized/trapped
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Reversible two tissue compartment model with plasma input
Blood
Tissue
PET
K1
k2
K1=E x F, E=extraction and F=flow=perfusionBP=k3/k4 (sum of specific and ‘slow’ non-specific bindingVd= K1/k2 x (1+BP)
Free Bound
k3
k4
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Reference tissue models
A reference tissue time activity curve (TAC) is used as input in stead of plasma input
R1=K1/k2=K1’/k2’=relative flow distributionBP=k3/k4=‘specific’ binding
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Presentation
• Physics and principles of PET- general introduction- overview of (neuro-receptor) tracers- positron emission and coincidence detection
• PET pharmacokinetic analysis- principles of kinetic modelling- generation of parametric images
• SPM example of assessment of (neuro-) receptor change
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Parametric pharmacokinetic modelling
Dynamic scanParametric image representingbinding of tracer in tissue
Purpose: generation of image representing distribution of PET pharmacokinetic parameter: glucose consumption, DNA synthesis, perfusion etc etc.
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PET pharmacokinetic parametric methods
• Parametric=pixelwise=voxelwise, i.e. calculation/modeling is performed per pixel/voxel
• A 3D PET image (volume) consists of ~106 voxels
• Ergo, parametric methods need to be fast
• Most parametric methods use ‘tricks’ to gain computational speed (linearisation,basis function method, (multi-) linear plots)
• Parametric methods are fast calculations performed for each voxel (independently).
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Parametric kinetic modelling(1) basis function and linear methods
Blood flow model example
Cb, CpK1
k2
Ct
CtkCpKdt
dCt21
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2 solutions for differential equation:- convolution:
- linearization:
Theory
CtkCbKdt
dCt21
tkpt eCKC 2
1 tVF
pdeCF )/(
tpt CkCkC 21
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Theory(Basis function method)
bbtVF
bbROI CVeCFVC d )/()1(
tVFb
deC )/(
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Theory(Basis function method)
1. Determine F and Va for each basis function using linear least
squares fitting (GLM)
2. Calculate sum of weighted squared difference (Xsqr) for each basis function, F and Va
3. Minimum amongst Xsqr provides ‘best fit’ for F, Va and basis function (=F/Vd)
aatVF
aaROI CVeCFVC d )/()1(
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Theory(linearization, linear least squares)
soeeeeROI
ROI
V
k
k
tCbtCttCp
tCbtCttCp
tC
tC
2
11111
)()()(
.....................
)()()(
)(
.......
)(
Y = X (+ ) =X-1Y in theory, but not possible due to noise
LS solution (GLM):=[XTX]-1XTY
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Results – Clinical evaluationExamples of parametric CBF images –
various method
BFM GLLS LLS
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Examples of parametric images
B C D
E F G
A
A=LoganC=Ichise 1D=Ichise 2E=Ref.LoganF=RPM1G=RPM2
Each voxel value represents the value for a pharmacokinetic parameter (Vd or BP)
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Presentation• General introduction NM and PET• Physics and principles of PET
- principles- overview of (neuro-receptor) tracers- positron emission and coincidence detection
• PET pharmacokinetic analysis- principles of kinetic modelling- generation of parametric images
• SPM example of assessment of (neuro-) receptor change
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Example of use of parametric PET data for SPM analysis
PET studiesDynamic [11C](R)-PK11195 PET studies of 10 young and 10 elderly healthy control subjects.
Scans were acquired in 3D mode using an HR+ scanner (Siemens). A neuro-insert was used for additional shielding for outside field of view activity.
Kinetic modellingParametric binding potential (BP) images were generated using Ichise linearisation of the simplified reference tissue models using a cerebellum time activity curve as reference tissue input.
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Example of PK11195 BP image
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Difference between anatomical VOI and SPM
Yellow = Thalamus (& pulvinar) VOI defined on MRIRed = SPM VOI
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Effect of VOI method on observed changes in PK11195 binding
-0.05
0.05
0.15
0.25
ANA (A1) PVE (A2) BP>0 (D1) BP-Man (D2) SPM* p>0.01(D3)
VOI method
BP
Young
Old
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SPM based on parametric PET data
• SPM might be used to more precisely locate areas of interest and to avoid that VOI are “contaminated” with regions without change.
• Data driven VOI provide a higher sensitivity for assessing (changes in) receptor binding.
• A drawback of data driven VOI, however, is that they depend on the data being used. Both sample size and statistical quality will affect size and shape of the VOI.
• Consequently, data driven VOI strategies may be less reproducible across studies and subjects than anatomically based VOI.