Outline Positron Emission Tomography - Institute of...

7/16/2009

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Mayneord-Phillips Summer SchoolSt Edmund Hall, University of Oxford

July 2009

Positron Emission TomographyPositron Emission TomographyPhysics & InstrumentationPhysics & Instrumentation

Dimitra G. Darambara, Ph.DMultimodality Molecular Imaging

Joint Department of PhysicsRMH/ICR

[email protected]


July 2009

OutlineOutline

• Introduction• PET Physics overview• Types of events• Acquisition modes• Detectors• Performance parameters• Data reconstruction and corrections• Detector developments• New development in PET


July 2009

Medical Imaging TechniquesMedical Imaging Techniques

• AnatomicalCT

MRI

US

• Functional or metabolicSPECT

PET

(f)MRI(S) (+probe)optical (SAI)

High resolution morphological capabilities with physiological info

Real-time physiological info

Biological processes

at molecular level


July 2009

PET in Medical ImagingPET in Medical Imaging• Powerful and sensitive means to

non-invasively investigate biologicalprocesses in-vivo

•• RadiotracerRadiotracer--imagingimaging techniquetechnique

• Inject tracer compounds labelledwith positron-emitting radionuclides

• Images of the static or dynamicdistribution of tracer

• Info on blood flow, metabolism,proliferation, angiogenesis, hypoxia,gene expression

In clinic:

Diagnosis, treatment follow-up,therapy assessment

Oncology,cardiology,neurology,psychiatry,treatment planning

Drug development


July 2009

PET: unique molecular imaging modalityPET: unique molecular imaging modality

3 main factors:• No need for heavy absorptive collimators higher sensitivity can detect and image nanonano-- and picoand pico--

molar levels of tracers inmolar levels of tracers in--vivovivo•• Absolute quantificationAbsolute quantification capability through accurate attenuation correction• Availability of β+-emitting radionuclides that are organic

atoms can be substituted in molecules without modifying substituted in molecules without modifying their biological activitytheir biological activity

PET radiotracers to investigate any biological process without interfering with normal biochemistry


July 2009

Positron Emission and AnnihilationPositron Emission and Annihilation

+

+

+

+

+

+

+

++

ν

e+

e+

e-

γ

γ

511 keV

511 keVProton decays to n, e+, ν

e+ combines with e-

and annihilates

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July 2009

Annihilation Coincidence DetectionAnnihilation Coincidence Detection• A molecular probe labelled with e+-emitting

radionuclides ⇒ annihilation-- simultaneous 2 x 511 keV gamma-rays-- 180°-- Line of ResponseLine of Response (LOR)-- electronic collimation

• Scanner: rings of position-sensitive photo-detectors-- millions of coincident pairs detected-- coincidence time windowcoincidence time window (6-12 ns)-- coincidence logic electronics – a “time time stamp”stamp” to the record of detected events-- scan time: 5-60 mins sensitivity, acquisition mode, size of ROI, amount of injected activity

• Reconstructed images of radiotracer distribution

e+ e-


July 2009

PositronPositron--emitting Radionuclidesemitting RadionuclidesIsotopeIsotope HalfHalf--lifelife Max E Max E

(MeV)(MeV)Range Range (mm)(mm)

ProductionProduction

C-11 20.4 mins 0.96 0.4 Cyclotron

N-13 9.96 mins 1.20 0.7 Cyclotron

O-15 123 secs 1.74 1.1 Cyclotron

F-18 110 mins 0.63 0.3 Cyclotron

Ga-68 68.3 mins 1.83 1.2 Generator

Rb-82 78 secs 3.15 2.8 Generator

Cu-62 9.74 mins 2.93 2.7 Generator

Cu-64 12.7 hrs 0.65 0.3 Cyclotron


July 2009

Positron Range Positron Range ------ NonNon--ColinearityColinearity

+

++

+

+

+

+

++

e+-emitting radionuclide

e+

e+ e-

511 keV

511 keV 511 keV

511 keV

e+ range

Effective e+ range

Non-colinearity

Error due to non-colinearity


July 2009

Positron Range Positron Range –– NonNon--ColinearityColinearity

• 2 fundamental limits of spatial resolution: 2-2.5mm for clinical whole-body scanners

•• Positron RangePositron Range : --- its distributions have exponential shape with long tails ⇒not well described by Gaussian function rms effective rms effective rangerange better indicator than FWHM--- radionuclide-specific, depends on positron emission E

•• NonNon--ColinearityColinearity :--- can be described as an approximate Gaussian angular distribution around 180°with FWHM~0.5 °--- linearly dependent on the distance D between coincident detectors: R = 0.0022xDR = 0.0022xD


July 2009

Detected Events in PETDetected Events in PETA detected event in PET is valid if:• 2 photons are detected within a predefined electronic time

window coincidence windowcoincidence window

• The LOR between the 2 photons is within a valid acceptance angle of the scanner

• The E deposited in the detector by both photons is within the selected E windowselected E window E-gating technique around the photopeak in the E spectrum need for detectors with good E resolution v narrow E gate

Such coincidence events promptsprompts


July 2009

Types of Coincidence EventsTypes of Coincidence Events

TRUETRUE

RANDOMRANDOM

SCATTEREDSCATTERED

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July 2009


•• SingleSingle : a single photon recorded by a detector

•• True coincidenceTrue coincidence : detection of 2 singles from the same positron annihilation within the coincidence window

True Count Rate: T = Aεεεε2ΩΩΩΩcoin

Where A = activity concentration of the sourceε = detector detection efficiency for 511 keVΩcoin = solid angle for detection of coincidence

annihilation photons


July 2009


•• Random or accidental coincidenceRandom or accidental coincidence : detection of 2 singles from 2 different annihilations within the coincidence window

Count Rate: R = 2ττττNxNz

where 2τ the width of time windowN single event rate incident upon detector x and z

• High Random count rate impact on noise, dead time and pulse pile-up limit sensitivity


July 2009

Types of Coincidence EventsTypes of Coincidence Events•• Scattered EventsScattered Events : one or both of the photons from the

same annihilation have undergone a Compton interaction (body, detector, scanner gantry)

Count Rate: S = Aεεεε2ΩΩΩΩdwhere Ωd the solid angle for the FOV for coincidence scatter events

• Scatter and Random events undesirable source of background counts loss of contrast resolution and quantitative accuracy in final reconstructed image

• Can be reduced by narrowing E and coincidence window and limiting FOV activity

• Prompt Count Rate: Sum T+S+R


July 2009

Noise Equivalent Count RateNoise Equivalent Count Rate

• The performance of a PET scanner characterised by a figure of merit a trade-off between undesired contributions and scanner sensitivity NECR, defined as:

T2

T + S + kR• measured as a function of activity• meaningful way to compare performance of different

scanners• Factor k : 2 or 1 determined by whether Randoms

measured in a delayed time window and subtracted or estimated from the single count rate

NECR =


July 2009

PET Acquisition Modes PET Acquisition Modes

Interplane septa

2D2D

3D3D

Centre of FOV: sensitivity in 3D significantly greater


July 2009

PET Acquisition ModesPET Acquisition Modes

•• 2D Mode2D Mode : Interplane septaInterplane septa orthogonal to system axis prevent photons entering at oblique angles efficient rejection of photons scattered in the body reduce single-channel counting rate lower R rate min dead time losses

•• 3D Mode3D Mode : septa removed ⇒ data for all possible LORs significant increase (4-8 fold) in photon sensitivity but considerable increase in S and R rates and system dead time sensitivity: a triangular function peaked at the centre of FOV

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July 2009

PET DetectorsPET Detectors

Properties of ideal PET detector:• High stopping power for 511 keV photons• High spatial resolution• V good energy resolution to reject scatter events• V high timing resolution• Be inexpensive to produce

Possible detectors:• Proportional gas chambers• Semiconductors• Scintillators + photo-detectors (PMTs, semiconductor-based

photodiodes)


July 2009

Physical properties of commonly used scintillatorsPhysical properties of commonly used scintillators

Reproduced fromReproduced from D. Bailey, J.S. Karp, S. Surti, “Posi tron Emission Tomography”, D. Bailey, J.S. Karp, S. Surti, “Positron Emission T omography”, SpringerSpringer--Verlag, London, 2005, pp 31Verlag, London, 2005, pp 31

Inorganic crystals emit visible light photons

4 main properties: stopping power of 511keV, signal decay time, light output, intrinsic E resolution


July 2009

Single Crystal mounted on individual PMTSingle Crystal mounted on individual PMToneone--toto--one couplingone coupling

Scintillation CrystalPMT Front-end Electronics

511 keV γ-ray

γ photons convert to light photons, proportional to γ energy

Light converted to electrical signal and amplified

Registration and further processing of the signal

Crystal dimensions determine the spatial resolution

30mm depth, 10-30mm high (axial), 3-10mm width (in-plane)


July 2009

4 PMTs

30 mm

y

x

AB

CD

y =(A+B) – (C+D)

A+B+C+D

x =(B+D) – (A+C)

A+B+C+D

BGO or LSO

8x8 or 12x12 matrix

of 6x6x30 mm3 or 4x4x30mm3

Block DetectorBlock Detector


July 2009

Important Performance Parameters in PETImportant Performance Parameters in PETPhoton SensitivityPhoton Sensitivity :

• Ability to detect coincident photons emitted from inside the FOV

• Determined by: scanner geometry and stopping efficiency of detectors for 511 keV

• Denser, higher Z, thicker (longer) detector elements to improve the 511 keV stopping power (BGO)

• Scanner geometry defines solid angle covering object• Small diameter & large axial FOV high sensitivity scanner• The higher the sensitivity the better the SNR in the

reconstructed image• High stopping power reduction of parallax error


July 2009

Important Performance Parameters in PETImportant Performance Parameters in PETSpatial ResolutionSpatial Resolution :

• Positron range effect its extent depends on the range of Es of the emitted positrons and the medium

• Photon Non-Colinearity worse for larger systems

• Size of the photon detector element pixel size (4-6 mm in typical clinical systems)

• Directly affects the spatial resolution in reconstructed image

• Rsys = ( Rdet2 + Rrange

2 + Rnonc2 )1/2

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July 2009

Important Performance Parameters in PETImportant Performance Parameters in PETEnergy and Coincidence Time ResolutionEnergy and Coincidence Time Resolution :

Improved by:• Using crystals with brighter & faster light pulses• Using low-noise photo-detectors• Collecting a higher fraction of the light into the photo-

detector for larger electronic pulses

• Good E resolution narrow E window reduce S & R events without compromising sensitivity

• Good T resolution narrow time window reduce R events• Typical values: 25% FWHM at 511 keV, 3ns FWHM


July 2009

Important Performance Parameters in PETImportant Performance Parameters in PETCount RateCount Rate :

• For each signal registered ⇒ a finite processing time• If too many photons hit detector saturation of electronics

due to pile-up of more than one pulses• Pile-up depends on: scintillator decay time; effective

integration time of electronics; photon event rate seen by the detector

For best count rate performance:• Crystals with fast decay time• Detector with excellent T resolution• Fast processing electronics• Limited activity within the sensitive FOV


July 2009

Depth of Interaction (DOI) EffectDepth of Interaction (DOI) Effect• A photon hits the detector travels a short distance within

the detector material deposits its E in the detector• the detectors used in PET do not measure this point the

exact depth at which photons interact is unknown DOIwithin the crystal

• The measured position of E deposition projected to theentrance surface of the detector parallaxparallax errorerror

• For photons at oblique angles parallax error producessignificant deviations from real position blurring ofreconstructed image degradation of spatial resolution

• DOI depends on: dimensions of the detector element,source location, scanner diameter, crystal length


July 2009

Parallax Error due to DOI EffectParallax Error due to DOI Effect

Annihilation photon path

Assigned LOR


July 2009

DOI EffectDOI Effect• A thin crystal with high stopping power reduces distance

travelled by photons in the detector reduces parallax error

• But thin crystal reduces sensitivity• An accurate measurement of DOI within crystal required• Need for detectors with DOI measurement capabilities

•• Phoswich detectorsPhoswich detectors: stacking thin layers of different scintillators with different decay time on top of each other and implementing pulse shape discrimination

• Use photo-detectors at both ends of a thick (long) scintillator

• Depth sensitive detectors (e.g. CdZnTe) • Ongoing research


July 2009

PET Data ReconstructionPET Data Reconstruction

• mathematical algorithms to calculate 3D probe distribution volume from the 2D projection data

• 2 basic reconstruction schemes:

1.1. Analytic MethodsAnalytic Methods : • acquisition process, measurements, reconstructed image

as continuous functions (e.g. FBP)• Directly compute an inverse transform formula to convert

the recorded hits into an image• Require spatial frequency filtering to reduce statistical

noise resulting in a loss of spatial resolution• Linear, more computational efficient, fast and simple to

implement

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July 2009

PET Data ReconstructionPET Data Reconstruction

2. 2. Iterative MethodsIterative Methods :

• acquisition process, measurements, reconstructed image as discrete quantities

• start with an initial estimate of the 3D distribution and go through iterative modifications of that estimate until a solution is reached (e.g. MLEM)

• may incorporate statistical methods• Appropriate for photon count limited data & PET systems

with non-standard geometry• Allow an improved trade-off between spatial resolution

and• More computationally intensive


July 2009

Corrections for PET DataCorrections for PET Data

• There are several undesired physical effects inherent in the detection process of annihilation photons in PET

measured PET data must be corrected for these physical factors either before or during image reconstruction


July 2009

Photon Attenuation within the tissuePhoton Attenuation within the tissue

• Most important correction• For any given LOR, the attenuation depends on the total

path travelled by the 2 annihilation photons (the total total thicknessthickness of the body along that line) and is the same whether a point source (origin of the 2γ emission) is outside or inside the object

• Attenuation may be corrected for every LOR by measuring the total attenuation factor of an external radiation source that transmits activity through any LOR

• In clinical PET/CT ⇒ use of X-ray CT ⇒ the 511 keV attenuation coefficients determined from an appropriate scaling of attenuation coefficients measured at X-ray Es


July 2009

Detector Response NonDetector Response Non--uniformityuniformity

• Variations of the coincidence detection efficiency between LORs affect the image uniformity in PET

• Variations result from imperfections related to physical, geometric, mechanical and electronic properties of individual detector elements

• This artefact is normalised by measuring the non-uniform response for every LOR with an external radiation source and applying this normalisation to every measured data set for correcting them


July 2009

Detector Dead Time or SaturationDetector Dead Time or Saturation

• Dead time: the finite time required to process and record an event while no other events can be recorded

• Also includes pulse pile-up loss of counts• Causes loss in spatial and contrast resolutions• Saturation when the incoming photon flux is higher than the

system processing bandwidth allows• Dead time losses significant in high count rates with

continuous or block detectors

• An analytic model of the dead time/saturation to calculate the correction factors that applied to every LOR


July 2009

Random Coincidence EventsRandom Coincidence Events

• Cause loss in quantitative accuracy and contrast resolution• R effects worse for high count rates• Estimates of the R coincidence rate for every LOR are

obtained from measurements or calculations and aresubtracted

• or estimated from the single count rate• Single count rate as a function of time is required

• Common technique is to measure the count rate in adelayed time window where true coincidences areimpossible

• Then real-time subtraction for each LOR implemented inhardware

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July 2009

Scatter Coincidence EventsScatter Coincidence Events

• Cause degradation of quantitative accuracy and contrast resolution

• Worse for larger objects, higher γ rates, poor E resolution

• Using a narrow E window rejection of large angle S events but small angle S events still present

• Small angle S events are calculated for each LOR and subtracted

• Most promising scatter compensation use simplified Monte Carlo simulations to estimate the scatter distribution

• Time consuming but already practical implementation in commercial PET scanners


July 2009

Isotope DecayIsotope Decay

• Compensates for changes in tracer activity over time

• Knowledge of the half-time of the isotope as well as the time record of when each data acquired is required


July 2009

Partial Volume EffectPartial Volume Effect• Causes spatial resolution blurring• Due to the finite spatial resolution of the system and the

inherent sampling of discrete pixel image representation• reduces intensity for structures that are on the order of the

system resolution or smaller• The activity concentrations of such structures either over-

estimated or under-estimated depending on the regional distribution of the radioactivity

• Correction factor by measuring the intensity reduction effects vs structure size in a phantom with known activity concentration in spheres of various known diameters


July 2009

Detector DevelopmentsDetector Developments

• New scintillators with fast decay time, high light output, high stopping power

• PS-PMT and MC-PMT• Si PIN Diodes• APDs• SiPMs• CdZnTe• HpGe• Si microstrip


July 2009

Avalanche Photo Diodes (APD)Avalanche Photo Diodes (APD)

• In a single package or arrays• Compact size• Position sensitive• Large excess noise• Internal signal amplification, so

improved SNR• High quantum efficiency• Need for low-noise, fast front-

end electronics• Gain sensitive to small

temperature variations• and changes in applied bias

voltage• MR compatible

Reproduced from T.K. Lewellen, Phys Med Biol 53 (2008) R287-R317


July 2009

Silicon Photomultipliers (SiPM)Silicon Photomultipliers (SiPM)• Geiger-mode APD• High intrinsic gain• Low operating voltage• Excellent timing resolution• Single photoelectron sensitivity• Excellent SNR• Robustness• V low excess noise• MR compatible• Low cost, wide range of pixel sizes• Dead space between cells reduces

overall QE• Lower detection efficiency than APD

at short wavelengths• High dark current (cooling)

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July 2009

CdZnTeCdZnTe

• Direct conversion --- true semiconductor

• High density and effective Z high absorptionefficiency

• High intrinsic spatial resolution obtained by theelectrode pixellation – on the front and in thedepth – rather than cutting crystals

• High energy resolution (better scatter & randomrejection, multiple-isotope imaging, energy-resolved CT)


July 2009

CdZnTeCdZnTe

• Operate in room temperature

• High resistivity due to wide band gap low-leakage current low-noise characteristics

• Small system FOV

• versatile, flexible, light weight and configurabledetectors

• Compatible with MRI: operate normally with MRIacquisitions up to 7 and 9.4 T

• Multimodal detector (MRI/SPECT/PET/CT)


July 2009

Time of Flight (TOF) PETTime of Flight (TOF) PET• In TOF PET for each

annihilation event thedifference in arrival timesbetween the 2 coincidentphotons is also measured

• Images have higher SNR thanimages without TOF info

• Scintillators with v fast timingdecay, high light output andhigh stopping power (LSO,LaBr3)

• V fast electronics

• Potential to improve the imagequality in heavy patients (moreattenuation and scatter)

CT Non-TOF MLEM

TOF MLEM

Patient 1: colon cancer, 119Kg, BMI=46.5

Patient 2: abdominal cancer, 115Kg, BMI=38

Reproduced from J.S. Karp et al, J Nucl Med 2008; 49:462-470


July 2009

New DevelopmentsNew Developments• Multimodality Imaging

PET/CTPET/MR

• TOF PET

• Specific applications – dedicated systemsbreast, brain, prostate

• V high resolution pre-clinical imaging systemssmall animal imaging

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