Positron Emission Tomography

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Dept. of Nuclear Medicine & Molecular Imaging, University Medical Center Groningen, The Netherlandsdatu

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Positron Emission Tomography

TU Eindhoven, 3-10-2007

A.M.J. Paans

Nuclear Medicine & Molecular Imaging

University Medical Center Groningen


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Elements of Life PET-nuclide

Hydrogen 18F (110 min)

Carbon 11C (20 min)

Nitrogen 13N (10 min)

Oxygen 15O (2 min)


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PET: A multidisciplinary approach

Cyclotron radionuclides, simple formChemistry on-line/off-line synthesis

labeled compoundpurification

Pharmacy pharmaceutical quality, QCMedicine PET-scan

evaluation, compartment model

A joint effort/multidisciplinary approachChemistryMedicinePharmacyPhysics

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mSCX-MC17


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Nuclear Reaction Q-value Target Product

18O(p,n)18F - 2.4 MeV H218O 18F-

18O2 (+F2) 18F2 20Ne(d,α)18F + 2.8 MeV Ne (+F2) 18F2

14N(p,α)11C - 2.9 MeV N2 (+O2) 11CO2

16O(p,α)13N -5.2 MeV H2O 13NO3, 13NO2+ EtOH 13NH3

14N(d,n)15O + 5.1 MeV N2 (+O2) 15O2 15N(p,n)15O - 3.5 MeV 15N2 (+O2) 15O2


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Positron Emitters:Production and decay

proton14N

4He

11B

11Ce+


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Specific activity Theoretical: A (Bq) = N0 . λ

11C 9.2 x 109 Ci/mol = 340 TBq/µmol

13N 1.9 x 1010 Ci/mol = 700 TBq/µmol

15O 9.2 x 1010 Ci/mol = 3400 TPBq/µmol

18F 1.7 x 109 Ci/mol = 63 TBq/µmol

For comparison

14C 6.2 x 101 Ci/mol = 2.3 MBq/mmol

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“Hot cells” in the radiochemistry lab


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Robotics in radiochemistry


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FDG-module ready for synthesis


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nucleusβ+

range

Line of response

annihilation

detector

detector

Line of response

511 KeV

511 KeV

Coïncidenceelectronics

Detector rings

Annihilation & coincidence detection

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PET is a quantitative measurement (Bq/mm3) if

corrections are applied for:

- Dead time

- Attenuation (68Ga/68Ge, 137Cs, CT)

- Scatter (scatter fraction in 3D > 50% !!)


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Detector materials NaI BGO GSO L(Y)SO Density (g/cc) 3.67 7.13 6.7 7.4 Eff Atomnumber 51 75 59 66 Hygroscopic yes no no no Decay time (ns) 230 300 56/600 40 Rel light yield 100% 15% 25% 75% Energy resolution* 7.8% 10.1% 9.5% 10.% * Energy resolution is for single crystals


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8 x 8 matrix of BGO crystals per detector

64 BGO crystal elements per detector

4 photomultiplier tubes per detector

Photomultiplier Tubes (PMTs)

BGO Detector Block


m. . . producing a

unique combination of

signals in the four photomultiplier tubes (PMTs).

Patented light guides channel the scintillation

light . . .

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B

C

A

D

X = {(A+C)-(B+D)}/{A+B+C+D}Y = {(A+B)-(C+D)}/{A+B+C+D}


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Continuous detector construction

Pixelated-continuous PIXELAR technology:

• individual scintillating crystals• optically continuous lightguide• closely packed PMTs

This design ensuresa homogeneousresponse and lightcollection, which bestpreserves systemenergy resolution.

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Ecat Exact HR+


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Diagnostic

Imaging Workshop

Biograph: The imager for life

ECAT EXACT HR+: Highperformance PET scannerECAT Accel: High throughputPET scannerSiemens Somatom Emotion:High performance, spiral CT70 cm patient portOptimized bed designSiemens syngo-basedcomputer system

PET/CT

the Siemenssolution


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Resolution evolution in time


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ECAT HRRT at MPI Cologne

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Spatial resolution is determined by

- size detector elements

- filters applied in the reconstruction process

In practise:

4 - 7 mm FWHM, depending on scanner

sometimes ~ 10 mm FWHM due to filters used

(RAT-PET: 1 - 2 mm FWHM)


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Fundamental Limitations in Spatial Resolution

- Range of the positronsThe mean range varies from 0.6 mm (18F), 1.1 mm(11C), 1.5 mm (13N) to 2.5 mm (15O) or 5.9 mm(82Rb)- Non-zero momentum at moment of annihilationFinite angular width of 0.5o FWHM about themean angle of 180o


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Positron energies and ranges

Nuclide Eßmax Range Eßmean Range(MeV) (mm) (MeV) (mm)

11C 0.961 3.9 0.38 1.113N 1.190 5.1 0.48 1.515O 1.723 8.0 0.69 2.518F 0.635 2.3 0.25 0.652Fe 0.804 3.1 0.32 0.968Ga 1.899 8.9 0.76 2.975Br 1.740 8.1 0.70 2.682Rb 3.350 17. 1.34 5.9


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For a higher spatial resolution:

- Smaller crystals

- Correcting for parallax: DOI (Depth of Interaction)Pulse shape discriminationLSO/GSO, LYSO/GSO, LYSO, LuYAP

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Depth Of Interaction - DOI

without DOI with DOI


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Time Of Flight (TOF) measurement

Detectors A and B at distance 2d, source atdistance x from center

PA - PB = (d+x) - (d-x) dt = 2x/c

With x = 1 mm dt = 3.3 ps

Detectors that fast and sensitive to 511 keVdo not exist


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Time Of Flight (TOF) measurements

for 1 mm a Δt = 3.3 ps is the equivalent

~1987, LETI (Grenoble), TTV, BaF2 , Δt = 750 ps

2004, Siemens/CTI (Knoxville), LSO, Δt = 500 ps

2004, IRI (Delft), UPENN (Philadelphia)/Philips,

LaBr3 , Δt = 310 ps


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2D - set upn rings, 2n-1 planes

different sensitivities

16 rings16 straight planes15 cross planes

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how many rings coincidentthe “ring difference”


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Sensitivity from 2D to full 3D


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Count rates

Singels count rates

Coincident count rate: N = Ntrue + Nscatter + Nacc

Coincidence count rate: TrueAccidental: Nacc = dt . Ns1 . Ns2Scattered count rate depends on energy windowand geometry

Dead time correction: Singles basedAccidental coincidences: Delayed coincident

count rateDept. of Nuclear Medicine & Molecular Imaging, University Medical Center Groningen, The Netherlandsda

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Count rates

Noise Equivalent Count Rate or NEC

NEC = T2 / {T + 2fobjR + S}

T = True coincidentR = Random or accidental (Nacc) coincidentS = Scatered coincidentfobj = fraction of FOV subtended by object

NB: Scatter fraction is dependent on size andcontent object


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Measured with20 cm cylinderphantom

NEC rate is notunique, is function offobj & scatter

Dead timecorrectionup to 50%


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LSO has a short decay ---> high count rate capabilityN.B.: Electronics should be adapted

By adapting the FDG dose a higher throughputcan be realized

N.B.: In 3-D the patient size will influence scatterfraction and so the NEC-rate curve

In a PET/CT the transmission scan time is minimal

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Attenuation correction

I ~ exp(-µx1) . exp(-µx2) = exp(-µ (x1 + x2)) = exp(-µd)Dept. of Nuclear Medicine & Molecular Imaging, University Medical Center Groningen, The Netherlandsda

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Attenuation correction:

Classical: 68Ga/68Ge transmission sourcemeasured in coincidence

Singles measurement: 137Cs transmission sourcebetter statistics, translation to 511 keV

CT: Effective energy ~ 70 keVtranslation to 511 keV


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Diagnostic

Imaging Workshop

CT Attenuation Correction

Hybrid method:• segment bone in CT• scale bone by 0.44• scale other by 0.54

Photoelectric effect is higher in bone

Scaled CT scan PET emission scan

0

0,1

0,2

0,3

0 100 200 300 400 500Energy (keV)

μ/ρ(cm/g)

CT PET

Error

Original CT scanCourtesy of the University of Pittsburgh Medical Center

Attenuationcorrection

at CT energy(~ 70 keV)

at PET energy(511 keV)


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Mass Attenuation coëfficients µ/ρ (cm2/g)

Air H2O Muscle Bone

70 keV 0.178 0.195 0.194 0.242

511 keV 0.0870 0.0968 0.0960 0.0927

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Scatter fraction

2D: scatter fraction is 10 - 15%,depending on scanner

3D: scatter fraction will be ~ 30% in brain studies,can be > 50% in studies of thorax or abdomen

An individual correction has to be applied


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Jaszczakphantom

NOcorrections


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Jaszczakphantom

attenuationcorrected


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Jaszczakphantom

attenuation& scattercorrected

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Data reconstruction

- FBP or ML-EM (including dead time cor)

- Attenuation correction

- Scatter correction


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Data reconstruction

Data is generated by measuring accordingprojection lines, line integrals

Basic reconstruction is Filtered Back Projection(FBP) according to mathematics described byRadon (1917)

Maximum Likelyhood Expectation Maximization(ML-EM) is a iterative method that maximizes theprobability of the reconstructed image for a givenset of measured projection data.


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Data reconstruction

In PET ML-EM is successful because of Poissonstatistics

Problem of iterative methods: NO objectivestopping criterium and procedure will easygenerate artefacts

Advantage: If stopped at the correct moment, asuperior image quality with less noise

Disadvantage: the correct stopping criterium is nota general rule but has to be established perprocedure


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Reconstruction TechniquesIterative vs Filtered Back Projection (FBP)

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Each event is characterized by the combination ofa detector pair

This coincident detector pair is unique and calleda Line of Response or LOR

The data can be stored as event-by-event or listmode combined with timing information

The data can be stored in a sinogram, matrix of allLOR's, ordered according to angle and distanceto central axis


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Sinogram, displacement vs angle


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Lines of Response, LOR, ring difference


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Storage of raw data

The choise between list mode or sinograms isbased on size of data set

The number of LOR's in a 3D PET system can goup to 5x 109. A large part will be zero’s so listmode can be more efficient.

List mode also allows you for a replay into adynamic study

So: 2D-data sets: sinogram mode 3D-data sets: depends on scanner (LOR's)

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mData acquisition types

- List mode (event-by-event) *- Static study- Dynamic study- Whole body study

ECG-gating is an option

- Transmission study for attenuation andscatter correction

* Often not available (sometimes only as research tool),sometimes the standard acquisition but hidden


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List mode

All coincidences are list with timing informationECG-gating can be included

All options for reconstruction are opene.g. dynamic studies with different frame rates,

for including of motion correction, etc.

Typical in research environment


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Static study

A single frame during a certain time

Examples:

18FDG brain study of 10 min, 60 min after injection18F-DOPA study

Transmission scan for attenuation correction


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Dynamic study

For a quantitative study e.g. glucose consumption(FDG), blood flow (13NH3, H2

15O), protein synthesisrate (11C-tyrosine)

Frame rate depending on pharmacokinetics

Arterial blood sampling for the input functionand metabolite studies

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Whole body study

FDG-WB: the most frequent clinical studyReconstructed in 3D-volume Also Maximum Intensity Projections (MIP’s)

18FDG available since 1976FDG-WB from ~1995 and still increasing

Overlap between positionsMinimize number of positions for throughput


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Brain research

- Blood flow H215O, C15O2

}oxygen extraction- Blood volume 11CO, C15O

- Glucose metabolism 18FDG

- Tumor metabolism 18FDG,11C-amino acids

- Receptor density 11C-raclopride, 18F-DOPA, 18FESP

- Stimulus research H215O, 18FDG


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Brain tumor: Protein Synthesis Rate

11C-Tyrosine: oligodendroglioma


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Functional Neuro-anatomy: The Concept


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Visual stimulation vs rest


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Language Study: Functional Brain Imaging

Complex Dutch Sentense

Of hogere straffen waartegen rechters protesterendergelijke ongevallen voorkomen kan betwijfeldworden.

Ambiguous Dutch Sentense

Zij kunnen bakken met zulk deeg niet verplaatsen.


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Language localization in

case of left temporal lobe

arachnoid cyst


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FESP and medication


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Cardiac research

- Flow 13NH3, H215O, 82Rb

- Metabolism 18FDG,11C-fatty acids, 11C-acetate

- Hypoxia 18F-fluoromisonidazole

- Receptors 11C-CGP-12177


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13NH318FDG

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Bypass surgery: yes or no?

Flow at rest Flow at stress Glucoseconsumption


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ß-receptor in left ventricle

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Oncological research

- Tumor flow 13NH3, H215O

- Tumor metabolism 18FDG,11C-tyrosine, 11C-methionine,11C-thymidine, 18FLT

- Cytotostatic kinetics 11C-cytostatics

- Therapy monitoring Change in metabolism


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Therapy evaluation


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• Visual analysis

• Normalised uptake (SUV)

• Pharmacokinetic modelling

Data Analysis of PET Data


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Co-registration

CT-PET density/bone structures vs metabolism

fiducial markers (do they exist??)

mutual information maximization

MRI-PET protons/relaxation times vs metabolism

fiducial markers (do they exist)

MRI image segmentation to rCBF-imagescombined with PET H2

15O rCBF study

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Multi modality imaging

CT, X-ray density information

MRI proton density, relaxation times (T1, T2)

MRS 1H-spectroscopy, only larger volumesmulti nucleus spectroscopy (31P, 19F, 13C)

SPECT pharmacokinetics, 99mTc, 123I, 201Tl, etc

PET quantitative pharmacokinetics11C, 13N, 15O, 18F (NB: metabolites)


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Camera development: PET/CT

+ =

PET CT PET/CT

• Hardware fusion


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CT PET

Post-transplant lymphatic Disorder

• Detection and diagnosis

PET/CT: Application


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Post - therapyPre- therapy

PET/CT: Toepassingen

• Therapie-evaluatie

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pre-treatment post-treatment

Treatment planRT planning and response

Case: Female with bronchial CA for RTP.

Scan protocol: Standard whole-body PET/CT scan pre- and post-therapy. Pre- and post-therapy PET/CT can be registered using manual syngo-fusion tool. Findings:Evaluate extent of disease prior to RT. RT planning based CT or PET/CT. Evaluate RT response.Data Courtesy of University Essen (Dr s S Marnitz and S Mueller)


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µPET Focus 220


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µPET Focus 220

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MicroPET

rat - WB

FDG


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PET scan PET scan -- [[1111C]verapamilC]verapamil

• PET scan using human Siemens HR+ PET scanner

Adapted from: Hendrikse, N. H. et al. Cancer Res 1999;59:2411-2416

Control Cyclosporine A, 50 mg/kg


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PET scan PET scan -- [[1111C]verapamil, C]verapamil, µµPET Focus 220PET Focus 220

Cyc

losp

orin

eC

ontro

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Coronaal Sagitaal Transversaal


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PET scan PET scan -- [[1111C]verapamil, C]verapamil, µµPET Focus 220PET Focus 220

Control Cyclosporine

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Arc correction


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Sinogram, displacement vs angle

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Documents

Positron Emission Tomography