Novel High resolution SPECT Instrumentation Novel High resolution SPECT Instrumentation and Techniques for Molecular Imaging of Small and Techniques for Molecular Imaging of Small

AnimalsAnimalsF. Garibaldi - ISS-NIH, Rome, 4-6 June 06F. Garibaldi - ISS-NIH, Rome, 4-6 June 06

specific taskspecific task -detecting vulnerable plaquesvulnerable plaques in mice

what you needwhat you need -high resolution high sensitivity-high resolution high sensitivity detectors

key parameters: key parameters:

- - SNRSNR- FOV- FOV

- Sensitivity- Sensitivity - Spatial Resolution- Spatial Resolution

- simulations, prel. - simulations, prel. measurementsmeasurements

Summary and outlook

Molecular imaging with radionuclides :the Molecular imaging with radionuclides :the in vivoin vivo characterization and measurement of characterization and measurement of biologic processesbiologic processes at at

the cellular and the cellular and molecular levelmolecular levelIt sets forth to It sets forth to probe probe thethe molecular abnormalitiesmolecular abnormalities that are that are the the basis of diseasebasis of disease rather rather than than to image to image the end effectsthe end effects of of these molecular alterationsthese molecular alterationsThe rat and mousemouse host a large number of human diseases. Therefore one can study disease progression and therapeutic response under controlled conditionsPET (microPET) cannot attain the needed performances ! MRI doesn’t have the needed

sensitivity

Collaboration between ISS, JHU(B. Tsui), Jefferson Lab (S. Majewski)

Molecular Imaging Modalities

CTCT

Tissue Density, ZTissue Density, ZAA20-50 µm20-50 µm

-galactocidase-galactocidase0.1 µmole H / µmole 0.1 µmole H / µmole 3131PP

MRIMRI

AA

H ConcentrationH Concentration

MMFF

BOLD, DCEBOLD, DCE0.1 mm0.1 mm

UltrasoundUltrasound

StructureStructureAA FF

DopplerDoppler0.1 mm0.1 mm

OpticalOptical(Bioluminescence, (Bioluminescence, fluorescence)fluorescence)AA

TopographyTopography

MM

~10~1033 cells cells quantitativequantitative

µm to mmµm to mm

PET/SPECTPET/SPECT

RadiotracerRadiotracerMM

~1-2 mm~1-2 mm<10<10-12-12 mole mole

= = quantitativequantitative

FF

Unique !!

γ Imaging: Single Photon Detector Module

Patient injected with radioactive drug. Drug localizes according to its metabolic properties.Gamma rays, emitted by radioactive decay, that exit the patient are imaged.

1.CollimatorOnly gammas that are perpendicular to imaging plane reach the detector

2.ScintillatorConvert gammas to visible light

3.Photomultiplier Convert light to electrical signal

4.Readout ElectronicsAmplify electrical signal and interface to computer

5.Computer decoding procedureElaborate signal and gives image output

High ResolutionHigh Resolution High SensitivityHigh Sensitivity DetectorsDetectors key parameters

SNR (and contrast)

(spatial resolution)

€

SNR = S − BKGS

S = counts in ROI,

BKG = background

€

DRF = n(r ,z) = dxdyP(x,y)PSF (x− r )2 + y2[ ]1/ 2

,z{ }∫

€

IC = Max − BKGMax

Max = max. counts in tumor ROI

energy resolution plays only a secondary additional role in imaging breast under compression

they are correlated

FOV

Diffusive Wall

FWHM = 7.4 mm

Absorbing Wall

FWHM = 5.4 mm

Light Spread Function (LSF)Light Spread Function (LSF)

∑

∑

=

==channel

channel

N

1ii

N

1iii

c

XcX

€

c i = ith channel signal

X i = ith X channel positionGamma Emission X position

€

σX ∝σ X i

Np.e.

⇒ R i ≡ FWHMX ∝FWHMX i

Np.e.

CsI(Tl)

Bialkali PMT

Important parameters for detectability/visibility

- SNR

- Contrast

time (and modality)

pixel dim/n.of pixels

scintillator

electronics, DAQ

detector and collimation

modality (compression)

efficiency

. Uniformity of p.h.response (affecs the overall en res. and the energy window sel.)

spatial resolution

fotofraction

Bialkali PMT

uptake (radiopharmacy)detector intrinsic properties

Importance of pixel identification

good pixel identification is fundamental for correct digitization affecting spatial resolution and contrast

C8 strips

M16 (4 x 4) mm2M64 (2 x 2) mm2

STD[Xrec-Xreal] vs Anode Size for CsI(Tl) scintillator

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 1 2 3 4 5 6 7 8

Anode Size (mm)

STD[Xrec-Xreal] (mm)

pitch 1.0 mmpitch 0.8 mmpitch 0.6 mmpitch 0.4 mm

4096 Ch. -> 8192 Ch. (10-20 kHz)

Under study

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Projective coordinate electronics

1024 ch, 2 KHz

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NaI(Tl) 1.2 pitch

H9500 (3x3 mm2)

tum 8 mm

tumors: (5, 6, 7, 8,9,10,12)

uptake 1:10; breast 6 cm

NaI(Tl) 1.5 pitch; H8500 (6x6 mm2)

NaI(Tl) 1.3 pitch; H8500(6x6 mm2)

6 mm

7 mm

8 mm

SNR vs tumor dimension(10:1-breast 6cm-NaI 1.0-H8500(6x6mm2)

02468

101214161820

4 5 6 7 8 9 10 11 12 13t(mm)

SNR HX (H9500)

measurements confirm simulation

smaller scintillator pixel, higher SNR

anode pixel has to be small

measurements

but

6 mm tumors visible

Geant 4 simulation

- pixellated CsI(Tl) (0.8 - 0.4 mm pitch)- LaBr3 continuous (3 mm thick, different surface(s) treatment(diffusive vs absorptive)- 6 x 6 mm2, 3 x 3 mm2, 1.5 x 1.5 mm2

(PMT anode pixel size)

1000 counts/view/resol.elem.1 plaque = 10 mCi,10resol.elem.

aorta: ~ 2 mm diameter

plaque size: 0.5 x 1 x 4 mm3

system sensitivity: ~ 10 cps/Ci

detector area: 100 x 100 mm2

spatial resolution: ~ 500 m

Trying to Image apoptosis by proper tracer (e.g.99mTcINIC-Annexin-V)

Performances not good enough for imaging biological process in vivo in small animals (mice)

Man Rat Mouse

Body weight ~70 kg ~200 g ~20 g

Brain ~105 mm ~10 mm ~6 mm

Heart ~300 g ~1 g ~0.1 g

Aorthic cannula ~ 30 mm 1.5 – 2.2 mm 0.9-1.3 mm

(0.5 mm)man rat

0.6 mm pitch H95000.6 mm pitch Burle

Summary of CsI(Tl), pixellated

What about CsI(Na) ??

LaBr3 to be carefully evaluated

Scaling down (100 mm, 0.8 mm --> 50 mm, 0.4 mm)1/4 of detector area, 1/4 number of channels

butbut0.4 mm is very small !!

mouse doesn’t scale !

but multiply by ~ 4 (multipinhole) x 4(8) ( n. of modules)

snr = 30 ( 60 ) ===> plaque “visible”

snr calculation

simulation summary

sensitivity too small

sensitivity smaller than

required

Submillimeter spatial resolution (FWHM=0.93 mm) AND

High sensitivity (~850cps/MBq)

30 time pinhole already obtained

Both spatial resolution and

sensitivity still to be improved

Coded apertures

Smaller scintillator pixels (0.8 --> 0.6 mm) ==> smaller photodetector anode pixels

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recostruction possible in a deepth of focus as large as large as 4 cm !!

F. Cusanno et al. NIM A

A G = then

A G = Ô, in fact

There are decoding patterns G allowing:

Ô = R G = ( O × A ) G = O * (A G) = O * PSF

MeasurementsMeasurements60Co source, 122 keV

NaI(Tl) 1.25 pitch

H8500 (6 x 6 mm2)

CsI(Tl) 1.0 pitch

H9500 (6 x 6mm2)

CsI(Tl) 1.25 pitch

H9500 (3 x 3mm2)

measurements confirm simulations: small anode pixel is needed for small scintillator pixel (0.8 --> 0.6 mm --> high number of channels 1024 for 1 module! )

1.5mm thick LaBr3 attached to a H9500 PSPMT

Image of a 0.25mm slit. Chipped edge seen at left. Non-uniformities to correct.

Projection of the image of the slit. FWHM = 0.65mm

Measured energy resolution ~ 8% FWHM @122 keV

Active area

0.75 mm FWHM

Dead area

1.4 mm FWHM

Mcarlo FWHM = 0.615

Mcarlo FWHM = 0.8

LaBr3 continuous 1.5 mm thick + H9500 (3 x 3 mm2 anode); 3 mm thick + H8500(6 x 6 mm2)

3 mm mm thick LaBr3 attached to a H8500 PSPMT

Preliminary pinhole SPECT reconstruction results from the CsI detectorImages are displayed as MIP (maximum-intensity-re-projections) animations

Please use slide show mode to see the animation2 point sources APOE mouse (kidneys shown)

Flood image Sample projectionimage

ConclusionsConclusionsA solution for this challenging problem exists:

- good results with CsI(Tl) 1 mm pitch + H9500 100 pixels, spatial resolution 0.53 mm - 0.46 mm, FOV=33-25, = (22-39) cps/MBq

improvements needed? improvements needed? scaling down (50 x 50 mm2, 0.4 mm pitch, Burle photodetector (3x3 mm2)

->more compact, much less expensive

- 100 x 100 mm2 CsI(Tl) 0.8 (0.6) mm pitch with individual readout- careful evaluation of LaBr3 option (the advantage is better energy resolution

(very important if multilabeling shows to be possible and useful)- Fov, surface treatment, thickness, availability, cost- decisiondecision to be taken on the base of SNRSNR obtained with measurements (phantoms)Measurements for CsI(Na) 0.4 - 0.6 mm pitch, LaBr3 3 mm thick

10 x 10 cm2 vs 5 x5 cm2 (scaling down) (tomographic reconstruction will be decisive)Final layout on two steps next two years (if funding allows)

Invited talks

Invited talks a Congressi Internazionali

1.F. Cusanno. “High Resolution, High Sensitivity detectors for Molecular imaging with Radionuclides: the Coded Aperture option”. Milos (Grecia). Imaging technologies in Biomedical Sciences. September 2005

2. F. Garibaldi. “High Resolution, High Sensitivity Detectors”, Advanced Molecular Imaging Techniques in the Detection, Diagnosis, Therapy, and Follow-Up of Prostate Cancer, Rome, 6-7 December

3. Magliozzi ML et al “High Resolution, High Sensitivity Detectors for Molecular Imaging of Small Animals and Tumor Detection”. International Conference of Advanced Detectors. Como (Italy), October17-21, 2005

4. F. Garibaldi, “Molecular imaging: high resolution detectors for early diagnosis and therapy of breast cancer”. Milos (Grecia). Imaging technologies in Biomedical Sciences. September 2005

5. "Molecular Breast Imaging: first results from Italian National Health Institute clinical trials", to be presented at the International Conference "Fist European Conference on Molecular Imaging Technology (EUROMEDIM2006)” Marseille, France, 9 - 12 May 2006

6. E. Cisbani, “Imaging with radionuclides: a powerful means for studying biological processes in vivo",  Fist European Conference on Molecular Imaging Technology (EUROMEDIM2006)", Marseille, France, 9 - 12 May 2006

- Cuba ?

Publications1. F. Garibaldi et al. “A PET scanner employing CsI films as photocathode”, Nucl. Instr. Meth., 2004, A525,

263-267.

• F. Garibaldi et al. “Novel design of a parallax free Compton enhanced PET scanner”, Nucl. Instr. Meth., 2004, A525, 268-274.

3. R. Pani, M.N. Cinti, F. Cusanno, F. Garibaldi et al“Imaging detector designs based on Flat panel PMT”, Nucl. Instr. Meth., 2004, A527, 54-57.

• F. Cusanno et al. “Molecular imaging by single-photon emission”, Nucl. Instr. Meth., 2004, A527, 140-144.

2. F. Cusanno et al. “Preliminary Evaluation of Compact Detectors for Hand-Held Gamma Cameras”, Physica Medica, 2004, XX (2), 65

3. Pani R. Cinti, M.N., Cisbani, E.; Colilli, S.; Cusanno, F.; De Vincentis 6. Preliminary study of metabolic radiotherapy with 188-Re via small animal imaging, A. Antoccia, G. Baldazzi, M. Bello, D. Bernardini, P. Boccaccio, D. Bollini, F. de Notaristefani, F. Garibaldi, G. Hull, U. Mazzi, G. Moschini, A. Muciaccio, F.-L. Navarria, V. Orsolini Cencelli, G. Pancaldi, R. Pani, A. Perrotta, M. Riondato, A. Rosato, A. Sgura, C. Tanzarella, N. Uzunov, M. Zuffa Nuclear Physics B, Volume 150, January 2006, Pages 411-416

4. Small animal imaging by single photon emission using pinhole and coded aperture collimation, Garibaldi, F.; Accorsi, G.; Fortuna, A.; Fratoni, R.; Girolami, B.; Ghio, F.; Giuliani, F.; Gricia, M.; Lanza, R.; Loizzo, A.; Loizzo, S.; Lucentini, M.; Majewski, S.; Santavenere, F.; Pani, R.; Pellegrini, R.; Signore, A.; Scopinaro, F.; Veneroni, P.; IEEE Transaction on Nuclear Science, Volume 52, Issue 3, Part 1, June 2005 Page(s):573 – 579

5. New Devices for Imaging in Nuclear Medicine, Cancer Biotherapy & Radiopharmaceuticals, 19(1), 121-128, 2004

6. A PET scanner employing CsI films as photocathode, Nucl Instr Meth A525, 2004, 263-267

10. Novel design of a parallax free Compton enhanced PET scanner Nucl Instr Meth A525, 2004, 268-274

11. A study of intrinsic Crystal-pixel light-output spread for discrete scintigraphic imagers modeling, Scafe, R.; Pellegrini, R.;

Soluri, A.; Montani, L.; Tati, A.; Cinti, M.N.; Cusanno, F.; Trotta, G,Pan Pani, R.;Garibaldi,F.,IEEE Transaction on Nuclear Science, Volume 51, Issue 1, Part 1, Feb. 2004 Page(s):80 - 84

12. Custom breast phantom for an accurate tumor SNR analysis, Cinti, M.N.; Pani, R.; Garibaldi, F.; Pellegrini, R.; Betti, M.; Lanconelli, N.; Riccardi, A.; Campanini, R.; Zavattini, G.; Di Domenico, G.; Del Guerra, A.; Belcari, N.; Bencivelli, W.; Motta, A.; Vaiano, A.; Weinberg, I.N.; IEEE Transaction on Nuclear Science, Volume 51, Issue 1, Part 1, Feb. 2004 Page(s):198 - 204

Publications

- Molecular imaging by single-photon emission”, Nucl. Instr. Meth., 2004, A527, 140-144.

- Preliminary Evaluation of Compact Detectors for Hand-Held Gamma Cameras”, Physica Medica, 2004, XX (2), 65-70

- Small Animal Imaging by Single Photon Emission Using Pinhole and Coded Aperture Collimation”, IEEE Tran Nucl Sci, 2005, 52(3), 573-579.

- Tumor SNR Analysis in Scintimammography by Dedicated High Contrast Imager”, IEEE Trans Nucl Sci, 2003, 50(5), 1618-1623

-Custom breast phantom for an accurate SNR analysis, IEEE Trans. N.S., Vol 51, N.1 Feb. 2004

- Molecular imaging: high resolution detectors for early diagnosis and therapy monitoring of breast cancer,To be published on NIM, Milos

-High Resolution, High Sensitivity Detectors for Molecular Imaging with Radionuclides: the Coded Aperture Option, to be published on NIM

- Euromedim Francesco

- Euromedim Evaristo

- Euromedim Carrato

-A. Dragone

1. “A PET scanner employing CsI films as photocathode”, Nucl. Instr. Meth., 2004, A525, 263-267.2. “Novel design of a parallax free Compton enhanced PET scanner”, Nucl. Instr. Meth., 2004, A525, 268-274.3. “Imaging detector designs based on Flat panel PMT”, Nucl. Instr. Meth., 2004, A527, 54-57.4. “Molecular imaging by single-photon emission”, Nucl. Instr. Meth., 2004, A527, 140-144.5. “Preliminary Evaluation of Compact Detectors for Hand-Held Gamma Cameras”, Physica Medica, 2004, XX (2), 65-70.6. “Small Animal Imaging by Single Photon Emission Using Pinhole and Coded Aperture Collimation”, IEEE Tran Nucl Sci, 2005, 52(3), 573-579.7. Milos code apertures8. Milos breast?9. Prostate Rome, in preparation10. Invited talks at Euromedim (titoli anche se non so se mettere il breast)11. Deleo et al (la PET del CERN sottomesso a NIM)12. altri lavori (recenti) di PET CERN)13. lavori dei nostri amici del pin diodes (IEEE CD?? )14. altra roba recente di Pani in cui ha messo solo me?15. Como M.Lucia

Invited talsk (presentazione a congressi):

1. Milos 20052. Milos 20053. Prostate Conference4. Euromedim a Maggio5. What else? (dal 2004)?6. Como MLuci7. Cuba?

Positron

Emission

Tomography

microPET

• Detection coincident events between two detectors

• Compton scatter equation relates scatter angle and Eo and Ere

• Photon direction is determined within conical ambiguity

Source

Image Plane

1st Detector

2nd DetectorScatteredγ - Rayσ

€

cosθ =1+ 511E0

− 511E0 − E re

Internal Compton Probe

Imaging Distance 10 cm

Compton ProbeHigh-Sensitivity Coll.High-Resolution Coll.

Efficiency Resolution 1.8e-3 2.47mm 1.11e-4 15.9mm 4.00e-5 10.5mm