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Imaging in Research

Imaging in Research. Gail Stevenson, DVM Radiology Center for Gamma Ray Imaging. Introduction. In vivo molecular imaging in small animals is the bridge between in vitro data and translation to clinical application

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Imaging in Research

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  1. Imaging in Research Gail Stevenson, DVM Radiology Center for Gamma Ray Imaging

  2. Introduction • In vivo molecular imaging in small animals is the bridge between in vitro data and translation to clinical application • Multiple longitudinal images provide more reliable information and reduce animal numbers needed. • No one imaging method is ideal for all studies.

  3. Cost vs. Value • Cost of animal • Cost of technician time • Cost of radiotracers • Cost of machine time • Value of your time • Value of your results

  4. Biomedical Imaging: The Big Picture

  5. Biomedical Imaging is mostly about mouse and rat models of human disease Normal Myocardial Infarct Myocardial Infarct Normal Clinical Images of Humans Laboratory Images of Rat Models SPECT 99mTc-Sestamibi Myocardial Perfusion Scans

  6. Convergence Biology/Medicine Physiology Genomics Proteomics Cellular Biochemistry Immunology Mouse models Technology Materials Science Detection Physics Electronics Computing Power Mechanics Instrumentation Imaging Science Modeling Reconstruction Optimization Estimation Techniques Calibration Methodology An interdisciplinary endeavor!

  7. Principal Biomedical Imaging Modalities • Magnetic Resonance Imaging (MRI) • Ultrasound (2D and 3D) • Optical Imaging • Microscopy • Fluorescence Imaging • Bioluminescence Imaging • Coherence Tomography (OCT) • X-ray Computed Tomography (CT) • Single Photon Emission Computed Tomography (SPECT) • Positron Emission Tomography (PET) Research universities, are investing in multimodality laboratories that provide their basic scientists with access to most if not all of these techniques.

  8. Stationary camera(s) Mouse rotates about vertical axis Pros: Simplest arrangement Cons: Abnormal position for mouse Measured or modeled PSF must be rotated during reconstruction One (or a few) Camera Design Options • Stationary mouse • Camera rotates about horizontal axis • Pros: • Mouse in normal position • Cons: • High precision motion required with possibly heavy camera(s) • PSF probably needs to be modeled

  9. Anatomical • Functional

  10. Molecular Imaging Components • Requires the administration of an image-altering substance known as the contrast agent • Contrast agent must be able to bind or activate • 3 components • Molecular target expressed within animal • Reporter which enables detection of the contrast agent by an imaging modality • Targeting ligand which enables the contrast agent to bind to the molecular target

  11. Exogenous Contrast: The Tracer Principle Basis for molecular imaging George Charles de Hevesy (1885 – 1966) 1943 Nobel Prize in Chemistry Molecular target becomes a signal source (photon pairs) Tracer should not affect target or organism Label Ligand

  12. Computer Tomography • Various tissue types absorb X-rays differently as they pass through the body • High anatomical resolution • Probes are iodine or barium-based and are needed for molecular capabilities • Probes increase radiation damage • Increasing the duration of exposure increases sensitivity and spatial resolution. • Both these later factors limit repeat imaging due to radiation dose.

  13. FaCT: Adaptive CT On-board Computer Static Counterweight Electronics X-ray Source Dynamic Counterweight Translating Beam Detector

  14. Low-Mag Mid-Mag Hi-Mag FaCT Sample Projections

  15. Optical Imaging • Employs light emission (photons). Two main forms: fluorescence or bioluminescense. • Can employ bioluminescence probes, near-infrared fluorochromes, and red fluorescent proteins. • Works primarily for structures near the surface.

  16. Optical Imaging with the Window Chamber Attached to a dorsal skin fold. Cover slip replaces one section of skin. Creates a ~2-D environment for implanted tumors.

  17. visible light excites the area and a camera or fluorescent microscope detects it. Does not require administration of a substrate, so no tail vein injections. Fluorescence Molecular Tomography (FMT) employs a continuous pulse light and multiple detectors resulting in a 3-D image. Fluorescence

  18. A fluorescent tracer, SNARF-1, has a pH-dependent spectral response. SNARF-1 Ch.3 Ch.2 Optical pH Imaging of an Invasive Tumor Calibrated ratio provides image of local pH, showing highly acidic tumor microenvironment Separate fluorescence images Courtesy of A.F. Gmitro, S. Moore, R. Gatenby

  19. Bioluminescense • Light emission does not require excitations of a reporter. • Light originates from a substrate reaction which releases photons. • Commonly transfect with one of the luciferase family (usually from firefly). And luciferase protein can catalyze reaction. • Give the animal D-luciferin by IV or IP injection at saturating levels for the luciferase reaction • Detects lower limits of light • Ten-fold decrease for every centimeter of tissue depth • Catalytic reaction is time and enzyme-dependent so window for optimum image capture (usually image within 15 minutes for up to 60 minutes) • Images are generally overlaid black and white photos of the mouse taken at the same time to determine location.

  20. Ultrasound • Formed by interaction of sound with subject • Transducer produces acoustic energy • Acoustic energy is attenuated and reflected by structures • Impedence appears brighter (cysts are dark) • Instantaneous results • No radiation

  21. Magnetic Resonance ImagingMRI • A large magnet generates a field around the subject. This causes hydrogen atoms to align themselves in water (dipole). Coils around the animal generate a temporary radio frequency pulse that can change the alignment of the dipoles.When the pulse stops, the dipoles relax to normal. The parameters are different for different tissues. • Modified techniques extend the capability. Gadolinium can be a nonspecific probe, or can become a targeted probe when labeled.

  22. MRI Advantages and Disadvantages • Expensive to purchase, install, and operate, requires technological expertise • Low sensitivity in many applications, can be improved with appropriate contrast agents • Requires cooperation of patients (patients must remain very still), can require sedation • Limited space inside magnet, claustrophobia and obesity can be problematic • Pacemakers and metallic (especially ferrous) implants need special consideration and can prevent scanning • Magnetic field requires special safety precautions, potential for disaster if a large piece of metal gets too close (iron O2 tanks) • No ionizing radiation • Non-invasive, does not require a contrast agent (although agents are used to improve contrast and sensitivity in some cases) • MRI is very flexible, can produce an amazing variety of images for different applications • MRI can produce ‘slice’ images of arbitrary orientation without moving the patient or machine • Excellent for obtaining contrast in ‘soft’ tissues (not as good with bones, cartilage, etc.)

  23. BIOSPEC 4.7 Tesla (Avance) -40 cm gradient coil system (S116) (15 gauss/cm) HARDWARE I

  24. AMX400 WB 9.3 Tesla HARDWARE II 40 mm gradient coil system (100 gauss/cm) Dual/single tune inserts Micro 2.5

  25. Advertisement Biological Magnetic Resonance at the University of Arizona Facility: 1.5 T whole body MRI scanner 4.7 T MRI/MRS scanner 7.0 T MRI/MRS scanner (summer 2007) 9.4 T MRI/MRS system 11.7 T NMR spectrometer

  26. Un-anesthetized acclimated, operant conditioned SCID mouse chocolate milk delivery system

  27. EMBRYOS IN SITU (9.3 Tesla) - 150 mm isotropic resolution - 3D RARE (T2 weighted)

  28. Alzheimers Disease, Fixed brains APP/PS1 model of Alzheimer’s Disease Control mouse 32 Dark spots in grey matter of APP/PS1 mouse are likely deposits of amyloid plaques

  29. Positron Emission TomographyPET • PET isotopes emit beta + radiation (positrons); each positron undergoes an annihilation reaction with an electron which results in the generation of two photons (high energy) that are detected and converted into visible light. • Isotopes last from minutes to days (18F=110 minutes) • 18FDG (18-fluorodeoxyglucose) is well-known. Accumulates where there is glucose uptake. • Probes are in nanomolar concentrations so little interference with biological processes.

  30. Useful Radioisotopes Designation Main Emission Half-life Chemistry 18F positron 2 hrs 15O positron 2 min 11C positron 20 min 64Cu positron 12.7 hr PET

  31. Single Photon Emission Computed Tomography (SPECT) • Differs from PET as isotopes are direct gamma emitters in a single direction. • Typical isotopes are 123 Iodine 99mTechnetium. • Isotopes have a longer half-life than most PET isotopes, making it easier to do studies. Half-life of technetium is 6 hours.

  32. CGRI SPECT Systems FastSPECT I SPECT/CT SemiSPECT FastSPECT II Spot Imager M3R FaCT Adaptive System LumiSPECT ModCam

  33. Some Useful Radioisotopes Designation Main Emission Half-life Chemistry 99mTc 140 keV Gamma 6 hrs 123I 159 keV Gamma 13 hrs 125I ∼30 keV X 60 days 131I 364 keV Gamma 8 days 111In 171 & 245 keV Gamma 3 days 133Xe 81 keV Gamma 5 days 67Ga 185 keV Gamma 3 days 201Tl 77 keV X 3 days SPECT

  34. Anesthesia Anesthetics affect experiments Experiments affect anesthetics

  35. Evolution of Mouse Imaging Holders Prone + Awake Supine + Anesthesia Opaque Nose Cone Electric Heater Current Imaging Method Original Method

  36. Multi-Camera Multi-Resolution System Five 1-mm pinholes Nine 0.25-mm pinholes Table-top four-camera SPECT system with interchangeable apertures Test bed to address the question: for a given task and ensemble of objects, what is best configuration? Hesterman et al., Med. Phys. 34(3), 987-993, 2007.

  37. Prototype Adaptive Imaging System • Interleaved stages to permit independent motion of camera and aperture assembly relative to object • Aperture enclosure contains microstage system for selecting pinhole from array of sizes Freed et al, Med. Phys. 35(5), 1912-1925, 2008.

  38. FastSPECT II → AdaptiSPECT • Key Features: • 16 cameras in 2 rings of 8 with adjustable radial position • 5 axis robotic stage for calibration and imaging subject positioning • Exchangeable cylindrical imaging apertures for choice of magnification/field-of-view • Listmode data acquisition architecture • Full dynamic imaging capability for periodic and non-periodic processes • Gigabit data link for compute-intensive processing on PS3 cluster • Raw data rate: 50 Gigabits/sec

  39. 18X Magnification FS II # of Pinholes Magnification Pinhole Sizes 3X Magnification FastSPECT II Imaging-Configuration Space Resolution Sensitivity Field of View

  40. AdaptiSPECT • Adjustable aperture • Motorized cameras

  41. AdaptiSPECT • Adjustable aperture • Motorized cameras

  42. AdaptiSPECT • Adjustable aperture • Motorized cameras

  43. AdaptiSPECT Aperture • Six aperture selections • Three center of FOV to pinhole distances • Two pinhole selections at each distance • Single pinholes • Quincunx pinholes

  44. Motivations • Study planning • ensure tissue of interest is in field of view • Localization • provide anatomical framework that supports interpretation of functional image • Complementary information • use second modality to show different process • Quantitation • provide information for scatter and absorption correction to permit derivation of absolute tracer concentration, for example

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