1 / 51

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.

gayle
Download Presentation

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

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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!

More Related