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Progress in Small Animal Imaging Roger Lecomte, Ph.D.

1 st European Conference on Molecular Imaging Technology Marseille, France, 9-12 May 2006. Progress in Small Animal Imaging Roger Lecomte, Ph.D. Department of Nuclear Medicine & Radiobiology. Molecular Imaging.

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Progress in Small Animal Imaging Roger Lecomte, Ph.D.

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  1. 1st European Conference on Molecular Imaging Technology Marseille, France, 9-12 May 2006 Progress in Small Animal Imaging Roger Lecomte, Ph.D. Department of Nuclear Medicine & Radiobiology

  2. Molecular Imaging • “… the in vivo characterization and measurement of biologic processes at the cellular and molecular level.”(Weissleder, RSNA 2000) • It sets forth to probe the molecular abnormalities that are the basis of disease rather than to image the end effects of these molecular alterations. • Imaging of specific molecular targets enables: • earlier detection and characterization of disease; • earlier and direct molecular assessment of treatment effects; • more fundamental understanding of disease processes.

  3. Why Small Animal Imaging? • The rat and mouse host a large number of human diseases • Opportunity to study disease progression / therapeutic response • under controlled conditions • non-invasively • in same animal • repetitively • Powerful tool for research into molecular pathways • Molecular targets, receptors & drug binding sites • Relationship between genes  phenotype • Gene expression & gene therapy assessment • Bridge between preclinical studies in animals and Phase I trials • PK/PD, ADME(T) • Study of site, specificity, mechanism of action of new pharmaceuticals • Preclinical study of dose regimen, toxicity,… • faster screening of investigational compounds (< time) • earlier decisions about compound’s suitability (< cost ) • smaller number of animals

  4. Molecular(?) Imaging Modalities A F Structure M A 0.1 mm Topography Doppler µm to mm ~103 cells  quantitative Tissue Density, Z A 20-50 µm M F Radiotracer A F M ~1-2 mm H Concentration <10-12 mole = quantitative 0.1 mm BOLD, DCE -galactocidase 0.1 µmole H / µmole 31P Optical (Bioluminescence, fluorescence) Ultrasound CT PET/SPECT MRI

  5. Outline • Animal / Molecular / Multi-modality Imaging • Overview of µPET, µSPECT and µCT • Some basic concepts • Existing technology • Multi-modality imaging • Today • In the future

  6. 18FDG 82Rb Courtesy University of Ottawa Heart Institute HR+ Allegro F. Bénard, UdeS Extent of breast cancer with multiples metastases (Whole-body FDG-PET scan, CTI/Siemens EXACT HR+) Clinical PET Imaging ~ 70 kg human  ~ 6-10 mm ~ 1 cc

  7. Normal 1 cm Infarct É. Croteau, UdeS APD PET microPET J. Cadorette, UdeS Whole-body FDG-PET scan 250 g rat (Sherbrooke APD PET Scanner) Rat PET Imaging 300 g rat  ~ 2 mm (  5 ) ~ 10 µl (  100 )

  8. 20 g mouse Coronal Sagittal Transaxial A. Aliaga, UdeS 28 g mouse J. Cadorette, UdeS Whole-body FDG-PET Scan20 g mouse(Sherbrooke APD PET Scanner) Transaxial slices Kudo et al., Circulation 2002: 106; 118-123 ~ 30 g mouse  ~ 1 mm (  2 ! ) ~ 1 µl (  10 ! ) Mouse PET Imaging

  9. Spatial Resolution in PET Positron range * Derenzo & Moses, “Critical instrumentation issues for resolution <2mm, high sensitivity brain PET”, in Quantification of Brain Function, Tracer Kinetics & Image Analysis in Brain PET, ed. Uemura et al, Elsevier, 1993, pp. 25-40.

  10. Spatial Resolution in PET Non- colinearity Positron range

  11. Spatial Resolution in PET d d/2 Geometric Non- colinearity Positron range

  12. Spatial Resolution in PET b Geometric Coding Non- colinearity Positron range Positioning accuracyIntrinsic resolution !!

  13. Spatial Resolution in PET Tomographic reconstruction 1.2<a<1.3 (a=0: no recons.) Physical limit Intrinsic b ~ 0.4 (scaled) d  0.8 mm b ~ 0 d ~ 1.2 mm Geometric Coding Non- colinearity Positron range For 1 mm : ( 1 µl ) 0.7 mm 0.7 mm (worst case) Individual detectors with independent readout/processing desirable !

  14. Coded Light Sharing Miyaoka et al, IEEE MIC 2000 MiCE Detectors (Micro Crystal Element) 0.8 0.8  6 mm3 MLS Crystals 5  5 array on 4 channels of 64-channel MC-PMT b ~ 0.4 mm  Intrinsic FWHM ~ 0.7 mm ! ~0.4 mm Positioning histogram

  15. Source size Non-colinearity Subtracted Intrinsic Spatial Resolution of PET Scanners

  16. FWHM = 1.21 mm Light/Charge Sharing vs Individual Pixels microPET II LabPET (Tai et al, PMB 2003) (Lecomte et al, SNM 2006) 2 mm pixels Individual APD Parallel digital signal processing 0.975 mm LSO 64-ch PMT + F.O. X-Y Analog decoding FWHM = 1.22 mm

  17. µPET Imaging in Mice No gating 32 g mouse 580 µCi, 60 min No gating End-systole 31 g mouse 1 mCi 18F- microPET II Yang et al, PMB 2004 & IEEE NSS/MIC 2004

  18. 1.35 1.7 1.0 2.0 0.75 2.4 LabPET™ Scanner Pixels 2210 mm3 LYSO/LGSO Resolution 1.35 mm or 2.4 µl Efficiency 1000 cps/µCi ( 2.6% ) Peak NEC > 2500 kcps Poster 191 http://www.advanced-mi.com/

  19. 1.35 1.7 1.0 2.0 0.75 2.4 LabPET™ Scanner • APD-based detectors • Parallel, all digital signal processing • List mode DAQ • High count rate, negligible deadtime • Ergonomic design • Proven reliability Poster 191 http://www.advanced-mi.com/

  20. Outline • Animal / Molecular / Multi-modality Imaging • Overview of µPET, µSPECT and µCT • Some basic concepts • Existing technology • Multi-modality imaging • Today • In the future

  21. Pinhole µSPECT Spatial Resolution in Pinhole SPECT Detector Rotating Object Pinhole • a : pinhole-detector distance • b : pinhole object distance • de : effective pinhole diameter • Ri : detector intrinsic resolution • M : magnification = b/a a b • No physical limit of resolution ! • Magnification enhances resolution • Sensitivity decreases as resolution improves • Long measuring time • Limited FOV • Images prone to distortions and artifacts

  22. Dedicated µSPECT PS-PMT + Array of NaI(Tl) 226 mm3 Imaging FOV: 125125 mm2 Square pinholes from 1 to 3 mm Spatial resolution: 1-2 mm FWHM 1-8 µl Sensitivity: 0.001-0.01% Pharmaceutical: [99mTc]-MDPDose: ~1 mCi Pinhole: 1 mm squareDistance (pinhole-center): 3.5 cmViews/Rotation: 128/360 degrees Acquisition time: 30 seconds/view or ~ 1 h McElroy et al, IEEE Trans Nucl Sci 49:2139–47, 2002 http://www.gammamedica.com/products/a_spect/spect.html

  23. Multi-Pinhole µSPECT U-SPECT-I based on a triple-head clinical SPECT system • 75 gold pinholes, 0.6 mm diam • Fixed object & camera, rotating multi-pinhole • Spatial resolution: 0.35 mm FWHM • 0.04 µl • Extended effective FOV • Improved sensitivity: 0.22% • Reduced measuring time: ~1-3 min !! Papillary Muscle Cylinder with 75 gold pinhole focused at the center of cylinder Cardiac perfusion study in mouse showing left (LV) and right (RV) ventricles according to 3 main axes (6 mCi 99mTc-tetrofosmin, 30 min acquisition at 30 min post-injection). (SNM Animal co-Image of the Year 2004) Beekman et al, 2004IEEE NSS/MIC,, Rome, October 2004 Beekman et al, 2005 IEEE NSS/MIC, Puerto Rico, October 2005

  24. µSPECT Imaging http://www.milabs.com/

  25. µSPECT Imaging http://www.bioscan.com/pdf/NanoSPECT-CT_Flyer.pdf

  26. µSPECT Systems Inveon SPECT/CT

  27. Outline • Animal / Molecular / Multi-modality Imaging • Overview of µPET, µSPECT and µCT • Some basic concepts • Existing technology • Multi-modality imaging • Today • In the future

  28. CT Measurement Process Transmission through tissues

  29. CT Measurement • Image Display: • CT numbers* or Hounsfield Units (HU) Black +1000 • Diagnostic quality ~5-10 HU (~1% SD) * From G. Michael, “X-ray computed tomography”, PhysicsEducation 36 (11), pp. 442-451, November 2001. White

  30. Principle of µCT DETECTOR • Digital X-ray camera • Phosphor (GOS) or CsI on CCD or CMOS photodiode or a-Si sensor matrix • MOS Flat panel • A-Se on TFT or CMOS readout array • Semiconductor pixel detector array* • Resolution: 10-100 µm • µfocus 10-100µm • W or Mo anode • 20-80 KV • 0.1-5 mA • Be filter CONE BEAM *B. Mikulec, “Development of segmented semiconductor arrays for quantum imaging”, Nucl. Instrum. Meth. Phys. Res.A510, pp. 1-23, 2003.

  31. µCT Spatial Resolution FWHMd: detector resolution FWHMx: projection blurring due to X-ray focal spot size x : pixel size Xf: focal spot size (FWHM) M : Magnification M = (dxs +dsd)/dxs Dx Xf *M.J. Paulus et al., “High resolution X-ray computed tomography: an emerging tool for small animal cancer research”, Neoplasia 2(1-2), pp. 62-70, 2000

  32. µCT Spatial Resolution MTFsys = MTFfoc MTFdet MTFsam MTFalg Resolution = (1/MTFsys 10%) / 2 FWHM G. T. Barnes, M. V. Yester, M. A. King, Optimizing computed tomography (CT) scanner geometry, Application of Optical Instrumentation in Medicine VII, SPIE Vol. 173 (1979)

  33. X-ray Energy in µCT Attenuation Coefficient vs Energy Contrast Resolution vs Energy* • At low energy (µ) contrast resolution limited by attenuation in subject • At higher energies (µ) contrast resolution limited by low absorption in subject • Best contrast resolution at energy for which µ ~ 2/D • For rats (D ~ 5-6 cm), Eopt ~ 30 keV • For mice (D ~ 2.5-3.0 cm), Eopt ~ 20 keV *M.J. Paulus et al., “High resolution X-ray computed tomography: an emerging tool for small animal cancer research”, Neoplasia 2 (1-2), pp. 62-70, Jan-April 2000.

  34. µCT Systems SkyScan-1078 ImTek MicroCAT II Stratec XCT Research SA GE eXplore RS

  35. Applications of µCT µCT Skeleton Image • Anatomy • Skeletal tissue • Adipose tissue • Thoracic imaging • Contrast enhanced soft tissue imaging • Vascular morphology • Abdominal tumor imaging • Renal morphology and function • Tissue density • Tissue composition http://www.imtekinc.com/html/skeletal.html

  36. Dose Considerations • LD50/30 for mouse: ~ 5 – 7.5 Gy • Doses 1-2 Gy produce radiation sickness and reduce nb of white blood cells due to bone marrow damage • Doses < 1 Gy induce some blood-cell destruction, free radicals, etc. • Doses in the range 5 - 200 cGy induce cell resistance to subsequent therapeutic doses of radiation (“adaptive response”*) • Doses in the range 1 - 20 cGy have been reported to induce therapeutic effects on certain tumor cells** • Current µCT typical exposure ~ 10-40 cGy / exam  Dose < 1 cGy * G.P. Raaphorst and S. Boyden, “Adaptive response and its variation in human normal and tumor cells”, Int. J. Radiat. Biol.75, pp. 865-873, 1999. ** D. Bhattacharkee, A. Ito, “Deceleration of carcinogenic potential by adaptation with low dose gamma irradiation”, In Vivo 15, pp. 87-92, 2001.

  37. µCT Imaging Protocol for Dose Reduction • µCT images should be acquired at lowest possible radiation dose • For longitudinal studies, maintain unirradiated control animals to eliminate radiation-induced effects as a confounding factor • Use of contrast agents can allow dose reduction in many instances by improving SNR and contrast ratio • Implement low-dose imaging protocols for screening at low resolution (~ few hundred µm) and perform high resolution µCT on selected euthanized animals for details • Physiologic motion prevents very high resolution (<100 µm) of alive animals

  38. Outline • Animal / Molecular / Multi-modality Imaging • Overview of µPET, µSPECT and µCT • Some basic concepts • Existing technology • Multi-modality imaging • Today • In the future

  39. Balb/c Mouse Tumor Apoptosis 64Cu-Annexin V Balb/c Mouse 64Cu-Phthalocyanine FDG PET/CT Scan J.E. van Lier UdeS N. Cauchon, UdeS T. Beyer, CTI PET Systems Anatomic Localization in Small Animals?

  40. Why Small Animal Multi-Modality Imaging? • Assess anatomy, physiology & biochemistry simultaneously • µSPECT/µPET provides information on metabolism, molecular target, receptor/drug binding sites • µCT provides information on tissue morphology, tumor volume, etc. • ET image enhancement and more accurate quantification • Anatomical reference for fusion with functional & molecular image data • Attenuation & scatter correction of ET images • Correction of partial volume effect • Initial estimate for iterative reconstruction of ET images (??)

  41. µCT in Molecular Imaging Context • Spatial resolution •  500 µm for anatomicallocalization • Contrast •  20 HU for soft tissue discrimination ( diagnostic) • Perfect co-registration to ET image in space & time • Simultaneous ET and CT image acquisition? • Fast image acquisition • Entire imaging session ~ ET imaging time • Small radiation dose • Small enough for repeated scans on same animal • Below threshold of “harmful” biological effects

  42. µPET/µSPECT/µCT Systems Inveon µPET/µSPECT/µCT microPET & µSPECT/µCT

  43. Multi-Pinhole µSPECT/µPET • 122 pinholes, 1 mm diam, 30 mm bore • Fixed object, detectors & multi-pinhole • Spatial resolution: 1.5 → >1 mm FWHM • No moving parts • Improved sensitivity: 0.5% • Reduced crystal light output • Singles acquisition • Alignment within scanner PET detectors Pinhole collimator Mouse imaged with 2.38 mCi 99mTc-MDP. Top: 2-D detector flood. Bottom: maximum intensity projections of reconstructed images. Acton et al, 2005IEEE NSS/MIC,, Puerto Rico, October 2005

  44. microCT/PET prototypeGoertzen, Meadors, Silverman, Cherry, Phys Med Biol 47; 4315-4328, 2002. Lead Shielding (1.5 mm) DEPARTMENT OF BIOMEDICAL ENGINEERING

  45. Simultaneous microPET/CT ImagingGoertzen, Meadors, Silverman, Cherry, Phys Med Biol 47; 4315-4328, 2002. 18F– scan of mouse. 700 Ci injected CT parameters: 40 kVp, 0.6 mA. Data collected over 400 views in a time of 40 minutes. DEPARTMENT OF BIOMEDICAL ENGINEERING

  46. PIXSCAN/ClearPET • XPAD3 photon counting detectors • Non-transaxial cone beam CT geometry • Simultaneous CT & PET imaging Delpierre, P. et al. PIXSCAN: Pixel Detector CT-Scanner for Small Animal Imaging, IEEE NSS-MIC 2005.

  47. Fused µPET/µCT • Scanner design: • LabPET detectors and electronics • Counting mode CT • X-ray rod source inside PET detector ring • Concurrent (simultaneous?) PET and CT image acquisition P. Bérard, Talk #190, Thursday, 16h R. Fontaine, Poster #180

  48. Conclusion • µSPECT revival with unprecedented resolution (0.04 µl) • µl resolution readily feasible, sub-µl resolution within reach in µPET • New fast pixel detector technologies paving the way for counting CT • Small animal imaging definitely evolving towards multi-modality • Combined small animal µPET/µSPECT/µCT imaging systems already available • Fusing modalities appears feasible

  49. Acknowledgements µPET/µCT Scanner Developments R. Fontaine & GRAMS Team, Faculty of Engineering, UdeS LabTEP Team, Faculty of Medicine, UdeS AMITeam, Advanced Molecular Imaging Inc.

  50. Merci ! Thank you!

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