2. Positron Emission Tomography

3. Outline PET Examples Imaging Goal Reconstruction/Data Requirements Method of Data Acquisition in PET –Positron Decay/Annihilation –Detectors/Scanner PET Tracers Data Acquisition Modes (2D/3D) Attenuation Degrading Effects Combined PET and CT

4. PET Scan Examples

5. PET

6. PET/CT FDG Breast Cancer CT PET Tracer: [F-18] FDG A glucose analog, Goes to regions of high metabolic activity.

7. Colon Cancer 10.9 mCi FDG 6 X ( 4 min Emission + 2.5 min Transmission) = 39 min

9. Figure 6. PET F-18 FLT images of a 56 year old male with a newly diagnosed GBM. (A.) Contrast MRI (left) and F-18 FLT (right). (B.) H&E stain of tumor (left) and MIB-1 antibody (right) to Ki-67 measuring the proliferation index ≈ 50%. (C.) Time activity curve for the arterial input function (red) and tissue counts of the lesion (yellow). (D.) Kinetic modeling diagram with 2 tissue compartments (K1=.165, k3=.012, Ki =.068).

10. MRI, T1+C FDG PET FLT PET (different patient) FDG – Glucose metabolism. Normal gray matter tissue has high glucose metabolism. FLT – DNA synthesis/cellular proliferation. Normal brain has low signal.

11. Dynamic Imaging / Kinetic Modeling During a scan, PET data can be acquired as a function of time with ~ arbitrarily good time resolution (limited by statistical/reconstruction considerations) Can use time sequence of tracer uptake (dynamic PET) coupled with blood pool tracer measurements to determine parameters in a model of tissue uptake. Leads to better understanding of mechanism of tracer uptake.

12. Dynamic Imaging / Kinetic Modeling Early time (Carotid Artery) Late time (Tumor)

13. Dynamic Imaging / Kinetic Modeling Possible 2-Tissue Compartment Model for Fluorothymidine (FLT) CaCa C1C1 C2C2 K1K1 k2k2 k3k3 k4k4 C a - Tracer concentration in blood C 1 - Unphosphorolated tracer concentration in tissue C 2 - Phosphorolated tracer concentration (preliminary step in the incorporation of thymidine into DNA) Model parameters Represent transfer rates between compartments (think pipe diameters) K’s: Significance example: In brain, K 1 is determined by BBB integrity whereas k 3, the phosphorolation/proliferation rate is expected to better reflect tumor status. These quantities cannot be cleanly disentangled with single time-point imaging.

14. Dynamic Imaging / Kinetic Modeling

15. Imaging Goal Main point: All nuclear medicine imaging studies involve administration of a molecule tagged with a radioactive atom (radiopharmaceutical or radio tracer). Purpose: As opposed to some other modalities, the purpose of nuclear medicine is to provide functional information. Contrast this with, for example, xray and CT procedures, in which we are mainly looking at structure. The particular function that we examine in a nuclear medicine mainly depends on the radiopharmeceutical used.

16. Imaging Goal Example: CT image of chest shows structure. Nuclear Medicine (PET) image shows metabolic activity. Tracer: [F-18] FDG CT imageOverlaid PET /

17. Overview of Image Reconstruction

18. We treat as a 2-dimensional problem

19. “2-dimensional” slice

20. Goal: Obtain image or map of some property (for example radioactivity distribution) of this patient. Constraint: Have to work from outside (no slicing allowed).

21. Line of Response (LOR): Definition: A line transecting the object.

22. With a complete set of LOR’s, every point in the object is intersected by lines in all directions.

23. Summary Input: integral of desired quantity for all LOR’s in object Output: map of quantity for entire object Nuclear Medicine In: Line integrals of radioactivity concentration. Out: Image of radioacitity concentration

24. An image of radioactivity distribution can be reconstructed if gamma-ray count rates are measured along “all” LOR’s. This can be done by collimated detectors (for example). The measured count rates are proportional to the total (integral) radioactivity along the LOR Example 1 - Internal Radioactivity

25. An image of radioactivity distribution can be reconstructed if gamma-ray count rates are measured along “all” LOR’s. This can be done by collimated detectors (for example). The measured count rates are proportional to the total (integral) radioactivity along the LOR

26. Example 1 - Internal Radioactivity An image of radioactivity distribution can be reconstructed if gamma-ray count rates are measured along “all” LOR’s. This can be done by collimated detectors (for example). The measured count rates are proportional to the total (integral) radioactivity along the LOR

27. Example 1 - Internal Radioactivity An image of radioactivity distribution can be reconstructed if gamma-ray count rates are measured along “all” LOR’s. This can be done by collimated detectors (for example). The measured count rates are proportional to the total (integral) radioactivity along the LOR

28. Example 1 - Internal Radioactivity  -ray detector Reconstruction Result: Map of radioactivity concentration Measure: Rate of  -ray emission along LOR* * emission rate is proportional to integral of activity concentration along LOR  (x,y) = Activity concentration

29. Reconstruction The point of this is – The data we need require that we know: 1. where an emitted gamma ray hits the detector; 2. the direction from which the gamma ray came. In SPECT we use collimators. PET uses a different technique to get the same information.

30. Method of Data Acquisition in PET

31. Initial State p n e+e+ Final State Positron Decay Closeup Beta Decay:  + This decay is not allowed for a free proton (energy conservation)

32. PET Some neutron deficient nuclei decay by positron emission (  + ) decay. Example: F-18  O-18 + e + + : Positron Emission Tomography Half life: 109 minutes

33. Positron - Electron annihilation Positron comes to rest (total distance traveled ~ 1mm) and interacts with ambient electron PET

34. Positron - Electron annihilation Result: Two back-to-back 511 keV photons traveling along a line that contains the point at which the annihilation took place. PET

35. In PET, the LOR upon which an annihilation took place is defined by the coincident observation of two 511 keV photons Gamma detectors Coincidence: Look for events within time τ of each other. (typical τ: 10ns)

36. The PET Scanner

37. PET

38. PET Detectors The PET scanner consists of a cylindrical grid of blocks, each containing a number individual detectors 15 cm (typical)

39. Block Detector Photomultiplier(s)Scintillation Crystals Gamma ray hits crystal It may interact producing scintillation light Scintillation light is detected by photomultiplier tubes (PMTs) Struck crystal determined by light distribution in PMTs Head on view

40. Example Block Detectors 6.4 mm x 6.4 mm 8x8 crystals/block 4.0 mm x 4.0 mm 13x13 crystals/block 6.3 mm x 6.3 mm 6x6 crystals/block 4.7 mm x 6.3 mm 8x6 crystals/block Most Common PET Scintillators: Bismuth germanate (BGO) Lutetium oxy-orthosilicate (LSO)

41. Open PET Scanner. Block detector housings are visible.

42. PET Nuclides and Tracers

43. Nuclidehalf-life C-1120.3 min N-1310 min O-15124 sec F-18110 min Rb-8275 sec e.g., 18 F  18 O + e + + Positron Decay

44. PET Compounds Routinely Produced and Approved for Animal/Human Use [O-15]H 2 O (perfusion) [O-15]O 2 (oxygen metabolism) [N-13]NH 3 (myocardial perfusion) [F-18]FDG (glucose metabolism, cell viability) [C-11]raclopride(dopamine D2 receptor ligand) [C-11]PMP(acetylcholinesterase substrate) [carbonyl-C-11]WAY100635(serotonin 5-HT1A receptor ligand) [C-11]flumazenil(central benzodiazepine receptor ligand) (+)[C-11]McN5652 (serotonin transporter ligand, active) (-)[C-11]McN5652(serotonin transporter ligand, inactive) [C-11]PK-11195(peripheral benzodiazepine receptor ligand) [C-11]β-CFT (dopamine transporter ligand) [C-11]PIB(beta amyloid imaging agent) [C-11]3-O-methylglucose(glucose transport) [C-11]DASB(serotonin transporter ligand) [F-18]FLT(thymidine kinase substrate, cell proliferation) [F-18]altanserin. (serotonin 5HT2A receptor ligand) [F-18] FMISO(tumor cell hypoxia)

45. PET Compounds Routinely Produced and Approved for Animal/Human Use [F-18]FDG (glucose metabolism, cell viability) FDG – FluoroDeoxyGlucose - a glucose analog FDG is now comercially available most places in the USA and throughout much of the world.

46. PET Data Acquisition Modes

47. Multiple Rings, 2D – 3D direct slices (n) For n detector rings: cross slices (n-1) total slices = 2n-1 2D 3D septa 3D- More counts 2D- Better ratio of good to bad counts

48. Notice! We are always going to produce a 3D image of radiotracer distribution in PET 2D and 3D PET refer to the method of acquiring the raw data used to produce the final image.

49. Attenuation and Attenuation Correction

50. The Problem: Attenuation of radiation by the patient In a nuclear medicine study a gamma-ray emitted within the patient may be reabsorbed. Thus the quantities that we measure for each LOR are not just integrals of the radioactivity distribution. Instead they are a complicated function of both the activity distribution and the patient attenuation properties.

51. Attenuation of Radiation by Matter For Photons (  and x radiation) –Total interaction probability is expressed by Linear Attenuation Coefficient:   --> Units = 1/cm   is a function of material and gamma energy –Transmitted beam intensity (# of photons) decreases exponentially with distance: Photon survival probability μ I0I0 x

52. Attenuation of Radiation by Matter If a photon is emitted here traveling along the indicated LOR then the probability that it will survive attenuation is The integral is taken along the LOR starting at the emission point to the exit point. Thus the probability of attenuation depends on the point of emission along the LOR.

53. Coincidence Attenuation Remember – in PET both photons have to be detected for an event to be registered. If you lose one photon you lose the event! Probability of the event surviving attenuation is the product of the individual survival probabilities. This makes attenuation a serious effect in PET, however …

54. Coincidence Attenuation Observe that P c is independent of where along the LOR the annihilation took place. Thus – each LOR has a particular attenuation factor! This is a very important difference from the single photon case.

55. Attenuation Correction In PET, we can make an “exact” attenuation correction by dividing the counts recorded on each LOR by the coincidence attenuation probability (or attenuation factor [AF]) for that particular LOR. Corrected Counts= (Recorded Counts)/AF (This is not true in SPECT.) Notice that the correction is applied to the raw data before or as part of the reconstruction.

56. Attenuation Correction positron (511 keV photon) source The required AF’s can be determined by performing a transmission measurement using an external radiation source. Sources are an integral part of a PET scanner.

57. Attenuation Corrected Not Attenuation Correction x-ray CT Attenuation Effects

58. PET Imaging Attenuation Effects Incorrect regional image intensity Distortion of shape Streaking from large hot objects can mask less intense structure Uncorrected Corrected

59. Degrading Effects

60. Scatter Randoms Limited Spatial Resolution Limited Counts -> Image Noise

61. Scattered Coincidence Event In-PlaneOut-of-Plane Scatter Fraction S/(S+T) With septa ~10-20% w/o septa ~30-80%

62. Scatter Control 1. Scattered events have energies less than 511 keV. Using a tight energy window eliminates some scatter events. However the energy resolution of scintillators used in PET (BGO, LSO, etc.) is not so great. Therefore if we make the windows too tight, we lose good events.

63. Scatter Control 2.There are several procedures for estimating the distribution of scatter in the PET raw data or images. The estimated scatter is then subtracted. Images for quantitative use must have a scatter subtraction performed.

64. Random Coincidence Event  R R =2  R a R b a b

65. Random Compensation Very good estimates of randoms can be made. Method 1: monitor the rates in the detectors to deduce the randoms rates. Method 2 – Delayed coincidence : For each detector hit, look for coincidences after a delay (i.e. look at the wrong time). There will be no true coincidences, only randoms.

66. Noise Due to counting statistics including the effects of scatter and random compensation More countsFewer counts

67. Correcting Background: Noise Equivalent Counts More background  more statistical image noise. “Background” What you measure What you want

68. Spatial Resolution Limits Detector Size Smaller crystal elements yield better resolution.

69. Spatial Resolution Limits Positron Range Positron moves before annihilation Size of effect depends on nuclide, typically on the order of a millimeter

70. Spatial Resolution Limits Opening Angle Gamma rays emerge with angles slightly different than 180 o due to center-of-mass motion of positron/electron pair. Angular blurring of few tenths of a degree. Effect on resolution proportional to ring diameter. Typical Resolution in a modern PET scanner 4-6 mm. (Not uniform throughout the field-of-view)

71. Combining Modalities PET and CT

72. PET/CT

73. PET/CT Systems All new systems sold in the USA are now PET/CT

74. Hardware fusion: function + anatomy FDG-PET PET/CT CT PET

75. Findings: Two foci of intense FDG uptake in soft tissue adjacent to bones consistent with malignancy. NHL-Better Localization Case: 53 y/o male with hx of NHL s/p chemotherapy with c/o weight loss and pain for follow-up PET/CT

76. Hardware fusion: function + anatomy A combined PET/CT scanner allows automatic correlation of functional image (PET) with anatomy (CT) The CT data can be used for producing the attenuation correction