Ronald Boellaard [email protected]

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Molecular Imaging using Positron Emission Tomography: Assessment of (neuro-)receptor changes with PET 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 Presentation

Transcript of Ronald Boellaard [email protected]

Page 1: Ronald Boellaard r.boellaard@vumc.nl

Molecular Imaging using Positron Emission Tomography:

Assessment of (neuro-)receptor changes with PET

Ronald [email protected]

Page 2: Ronald Boellaard r.boellaard@vumc.nl

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

Page 3: Ronald Boellaard r.boellaard@vumc.nl

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

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cc]

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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

Page 29: Ronald Boellaard r.boellaard@vumc.nl

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

Page 30: Ronald Boellaard r.boellaard@vumc.nl

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

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Tijd (min)

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tiv

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(k

Bq

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) 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

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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

Page 47: Ronald Boellaard r.boellaard@vumc.nl

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)

Page 56: Ronald Boellaard r.boellaard@vumc.nl

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

Page 57: Ronald Boellaard r.boellaard@vumc.nl

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

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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.