Positron emission tomography (PET) is a non invasive, diagnostic imaging technique for measuring the metabolic activity of cells in the human body. It is useful clinically in patients with certain conditions affecting the brain and the heart as well as in patients with certain types of cancer. The field of PET has been emerging into clinical diagnostic medicine and is approved by many insurance carriers for coverage. PET is unique because it produces images of the body's basic biochemistry or function. Traditional diagnostic techniques, such as x-rays, CT scans or MRI, produce images of the body's anatomy or structure. The premise with these techniques is that the change in structure or anatomy that occurs with disease can be seen. Biochemical processes are also altered with disease and may occur before there is a change in gross anatomy. This paper discusses about the equipment used in PET, including the cyclotron or generators to produce the PET drugs, the cameras that produce the images. It is a new scanning technique in medical research. PET allows us, for the first time, to measure in detail the functioning of distinct areas of the human brain while the patient is comfortable, conscious and alert. We can now study the chemical process involved in the working of healthy or diseased human brains in a way previously impossible. Without the advent of the PET scanner, we could only infer what went on within the brain from post-mortems (dissections after death) or animal studies. PET represents a new step forward in the way scientists and doctors look at the brain and how it functions.
INTRODUCTION:
PET is an imaging technique that is used to visualize some of these processes that change. Even in diseases, such as Alzheimer's disease, where there is no gross structural abnormality, PET is able to show a biochemical change. PET is a very useful addition to the clinician's diagnostic toolbox, providing significant advances to traditional diagnostic methods. A PET Scan is a simple procedure. It involves the use of a small amount of a radioactive material, similar to what is used in other nuclear medicine procedures. The radioactivity is attached or tagged to a compound that is familiar to your body. Compounds similar to glucose, water, ammonia, and certain drugs may be used. The radioactive drug is administered to the patient, usually by injection, and a specially designed PET scanner images how the body processes the drug. PET is useful in the diagnosis and management of patients’ cancer, with certain neurologic disorders, and with heart disease. Medical imaging is often thought of as a way of viewing anatomical structures of the body. Indeed, x-ray computed tomography and magnetic resonance imaging yield exquisitely detailed images of such structures. It is often useful, however, to acquire images of physiologic function rather than of anatomy. Such images can be acquired by imaging the decay of radio-isotopes bound to molecules with known biological properties. This class of imaging techniques is known as nuclear medicine imaging. The most common form of nuclear medicine scan uses a gamma- ray emitting radio-isotope bound to a chemical with known physiological properties.
PET for quantitative measurement of physiological variables:
A PET study begins with the injection or inhalation of a radio-pharmaceutical. The scan is begun after a delay ranging from seconds to minutes to allow for transport to and uptake by the organ of interest. When the radio-isotope decays, it emits a positron, which travels a short distance before annihilating with an electron. This annihilation produces two high-energy (511 keV) photons propagating in nearly opposite directions. If two photons are detected within a short (~10 ns) timing window (the coincidence timing window), an event (called a true coincidence if neither photon is scattered) is recorded along the line connecting the two detectors (sometimes referred to as a line-of-response (LOR)). Summing many such events results in quantities that approximate line integrals through the radio-isotope distribution. The validity of this approximation depends, of course, on the number of counts collected. For two- dimensional imaging, these line integrals form a discrete approximation of the Radon transform of a cross-section of the radio-isotope concentration, and can be inverted to form an image of the radioisotope distribution. If they are suitably calibrated, PET images yield quantitative estimates of the concentration of the radio-pharmaceutical at specific locations within the body. The kinetics of the pharmaceutical can be modeled as a linear dynamic system with the arterial concentration of radio-isotope in the blood as the input and the PET measurement as the output. The state variables are the concentrations in different compartments of the tissue, where examples of compartments would be blood, the interstitial space between cells, and the interiors of cells. Compartments need not be related to physical spaces, and can represent, for example, bound and unbound states of the radio- pharmaceutical. The exchange rates between the compartments are parameters of the
models. Acquiring a series of images sequentially after injection yields a time-course of the sum of the quantity of tracer in each compartment, i.e., of the output of the model, which can be used to estimate the model’s parameters. These parameters can then be used to calculate physiological parameters of interest, such as blood flow, glucose metabolism, receptor binding characteristics, etc. Thus, PET can be used for precise quantitative measurements of specific physiological quantities.
Sources of positrons:
A positron is an anti-matter electron. It is identical to the electron in mass, but has an opposite charge of +1. Positrons can come from a number of sources. However, in PET they are all produced by nuclear decay. Basically unstable nuclei are produced in a cyclotron by bombarding target material with protons. A typical reaction is to have a bombarding proton enter the nucleus of the target material and kick a neutron out in the process. For example, bombarding 18-O (an isotope of oxygen that has two extra neutrons relative to the familiar 16-O) results in the proton being captured and a neutron being ejected from the target nucleus. Changing the number of protons in the nucleus changes the atomic species and in this case the atom is changed from oxygen to fluorine. We can represent this as [18-O + proton => 18-F + neutron]. Other reactions are also possible, e.g., nitrogen to carbon with the participants being [14-N + proton => 11-C + alpha] (an alpha particle is composed of two protons and two neutrons). The new nucleus created in this manner is unstable and eventually decays into a more stable form. The time it takes for this decay to occur depends on the particular species created, and can range from the almost instantaneous to thousands of years.
In PET the target material is chosen so that the product of the bombardment decays to a more stable state isotope by emitting a positron. Taking 18-F above, the nucleus has too many protons in it to remain stable so one of these protons decays into a neutron and, in the process, emits a positron and a neutrino. This can be represented as [proton (+1 charge) => neutron (0 charge) + positron (+1 charge) + neutrino (0 charge)]. After the decay, we are left with 18-O again (the original target material), a positron, and a neutrino. The neutrino is an odd little particle which has no mass, no charge, and travels at near the speed of light. It can easily pass through a planet without interacting with anything so for all intents and purposes
once created, it is out of the picture. The positron on the other hand, being the anti-matter electron that it is, has a different fate in store for it.
The process on positron:
Left over energy from the nuclear decay process is shared between the positron and the departing neutrino. This energy takes the form of kinetic energy i.e. motion. Because of the need to conserve energy and momentum the positron is forced to hang around in this world - colliding with other particles and loosing kinetic energy - until it almost comes to rest. Once the positron has lost most of its kinetic energy it is ready to participate in the annihilation reaction. The positron will encounter an electron and, now free to obey the momentum/energy conservation laws, the two completely annihilate each other - converting all their mass into energy. The result of the annihilation process is two photons (light). Conservation of energy says that the system before annihilation (positron rest mass energy, electron rest mass energy, small bit of remaining kinetic energy) must be the same as the energy of the system following annihilation (two photons). Conservation of momentum dictates that the momentum of the system before annihilation - which is basically zero since the positron and electron are almost at rest - be the same as the momentum of they system following annihilation. The only final system state which is allowed under these conditions is one in which the two photons travel off in opposite directions (so the net momentum of the system is zero), and each has an energy corresponding to half the energy of the initial system. Since the rest mass of the positron and electron are identical (511keV), each photon has 511keV of energy. There is a small bit of kinetic energy and net momentum in the initial system when annihilation occurs, and this has to make its way into the final system. This is done by having the photons fly off at not quite 180 degrees from each other, and have energies a little off the ideal 511keV rest state annihilation value. However, for all intents and purposes these deviations are small and can be ignored.
The detection of photons:
The positron is now no more, and we have got two 511 keV photons flying off at 180 degrees from each other. The next step in PET is to detect these photons with a PET camera. Detecting the photons allows us to determine where they came from (the site of the
annihilation). Assuming that site is in close proximity to the nucleus which released the positron in the first place, we will have spatially located the site where that nucleus was when it decayed, and finding out where this nucleus goes in the body (riding the chemical compound we want to follow) is what the whole system is about.
Positron: Antimatter equivalent of the electron
Working:
fluorine is detected by the PET scanner and shows in fine detail the metabolism of glucose in the brain.
How much radiation does a patient get?
PET scans using radioactive fluorine in FDG would result in patients receiving exposures comparable to (or less than) those from other medical procedures, such as the taking of X- rays. Other scanning agents - for instance, 6-F-dopa or radioactive water - normally cause even less exposure.
Resolution Requirements
The use of PET in a clinical setting requires different characteristics and performance of the instrumentation, computer hardware and processing software than a system used in a research environment. The resolution in PET always has to be balanced against acceptable levels of image noise and patient throughput. For most clinical PET applications the intrinsic resolution of approximately 6 mm in all spatial directions seen today in most PET systems is adequate. At this resolution high quality images can be reconstructed at a final image resolution of 8-10 mm. These systems also have a sampling distance of approximately 3 mm in all spatial directions. The relatively uniform resolution and sampling in these systems makes them suitable for true 3-D volumetric imaging. This becomes a very important feature
in, for instance cardiac imaging, where it necessary to reorient the image data into long axis views.
Patient Throughput
In a clinical setting, one of the most important factors is patient throughput. One would like to set up the scanner quickly for a new patient, acquire the necessary data, reconstruct and process the data, generate a film for readout and reporting and, eventually, to archive the data. The system should also be able to collect data in a multitude of modes, including simple static, dynamic, gated, and rectilinear scans.
Field of View (FOV)
A PET scanner should not only be designed to image one single organ, such as the brain or the heart, but should be able to image any organ in the body, including whole-body scans. Most PET systems today are whole-body systems, i.e., they have a typical transaxial FOV of 60 cm. This FOV is adequate to handle most patients. The axial FOV of most PET systems today is limited to approximately 10 cm. This relatively narrow axial FOV imposes some limitation on the imaging procedures that can be performed clinically. It also requires more accurate positioning of the patient in comparison with conventional nuclear medicine procedures. For a clinical system, it would be desirable to extend the axial FOV to 15-20 cm. This would, for instance, allow full brain and heart imaging in a single frame and more efficient whole body imaging.
Retractable Rings
Retractable ring sources reduce the radiation dose to the technologist by decreasing the handling of the source.
Retractable Septa
Although retractable septa are not a must for a clinical system, with this feature the efficiency of the PET system can be improved through the acquisition of more coincidence planes.
Ring Planes
Current PET systems have up to 16 ring planes, producing a total of 31 transaxial planes. The resolution is about 5 mm in all directions. This resolution is adequate for most clinical applications. With a sampling of 3 mm in all directions, one can perform studies without any detector motions.
Count Rate Performance
A PET system used in a clinical setting should be able to handle wide range of count rates, without serious losses in resolution and count rate linearity. In most clinical study protocols, such as brain FDG scans or cardiac viability studies using FDG and NH3, the injected activity does not produce count rates high enough to reach the count rate limitations of the scanner. In high count rate studies, such as 82-Rb cardiac studies, the injected activity produces high enough count rates to produce significant dead time in the system. Most systems do have built-in dead time corrections, thus producing a linear response to injected activity.
Acquisition Software
In a clinical setting typically only a limited set of well defined study protocols are used. It is therefore desirable, for these procedures to set up standard protocols which automatically configures the scanner for acquisition and subsequent processing. By using these pre- defined configuration procedures, a study can be started quickly. The technologist does not have to enter a large number of parameters, such as scanning times, number of frames, reconstruction parameters and other processing parameters. By using these pre-defined protocols, the system is also less susceptible to human typing errors. In defining these "canned" protocols it is, however, important to allow some flexibility in changing parameters for special cases (e.g., study time, reconstruction parameters)
Processing Software
An important aspect of clinical PET is the necessity of fast and efficient processing software and hardware. After acquisition completion, the processing software should be able to produce a set of preliminary images before the patient leaves. The final images should, for most basic studies, be finished within 1 hour after scan completion. This requires that the processing software be highly automated and requires as little technologist interaction as possible. In a clinical PET center where 8-10 patients are scanned per day, it is very likely that there will be very little CPU time left on the acquisition computer system for processing of previously acquired studies. In order to be able to process all of the patient data, additional processing capabilities are necessary in the form of additional workstation(s). This in turn requires that the computers be networked to allow the data to be interchanged between the acquisition and processing systems.
Data Flow and Archiving
The flow of data generally proceeds from acquisition to archiving and, finally, to image analysis. In a basic PET study, such as a static FDG brain scan with 15 images, approximately 24 megabytes (MB) of data are produced (including attenuation correction, normalization, emission data, and images). Of this data only 0.5 MB contains the final image data (e.g. reconstructed images). In a clinical setting, it is unlikely that the raw data will be reprocessed after the final images have been produced. Image data is, however, frequently retrieved, usually for comparing multiple studies performed on a patient. It should, therefore, be necessary to store only image data in a form that can be retrieved within a few minutes. Raw data can, in contrast, be stored on media with a greater access time. For long-term storage of all files, including the raw data, high density, slower media such as 4 mm tape can be used. Tape allows for fast archiving and provides reliable storage at a very low cost. At the present time, the most logical choice for storage of image data is optical (or magneto-optical) disk. These disks are easily handled, and data can typically be retrieved within seconds after the disk is mounted. The ability to have fast access to the data becomes especially important in a setting where films have been replaced with computer displays. Image analysis and other application programs running on workstations can query the archive database for file information. Individual files can then be copied to a local disk on the workstation. The system should be able to collect data in a multitude of modes, such a simple static, dynamic, gated, and rectilinear scans.
Display of Image Data
One of the final steps in the processing chain of the PET study is to produce a final layout of the images for the diagnosing physician. The conventional way of presenting the image data is to produce a transparency film (x-ray film) of the images on the computer display. In addition to the image data, the film should also be labelled with demographic data about the study such as patient name and scan type. Since this information is usually stored in the image files together with the image data, the labeling and layout of the images on the display
can be automated in software. With the rapid development of local area networks, films may soon no longer be necessary. Instead, the images can be read from a display system located in the reading room, which has access to the PET image data through a computer network. Referring physicians do in most cases require a hard copy of the study; this can be accomplished using x-ray films. With recent improvements in printer technology, high quality color output may also be a low cost alternative to the traditional film.
Kinetic Imaging:
Kinetic imaging refers to the measurement of tracer uptake over time. An image of tracer activity distribution is a good starting point for obtaining more useful information such as regional blood flow or regional glucose metabolism. The process of taking PET images of radioactivity distribution and then using tracer kinetic modeling to extract useful information is termed image analysis. The tracer kinetic method with radio labeled compounds is a primary and fundamental principle underlying PET.
ROI Analysis
A region of interest (ROI) can be drawn over a segment of the myocardial wall on the last image (where the heart is well-defined) and then copied to all previous images so that the activity in that segment of the myocardial wall can be tracked over time.
Tissue Curve
Blood Curve
Data obtained from an ROI drawn over the left ventricle produces a blood time-activity curve. A biochemical or physiological model can be fitted to the blood curve in conjunction with a regional tissue curve to estimate one or more model parameters (e.g., myocardial blood flow) in that tissue region. The processing of PET images through ROI analysis and time-activity curve fitting with a particular model are a major component of image analysis. This
processing of PET images can often be facilitated by semi-automated software packages and can often be fully automated to produce parametric images. These images represent a parameter (e.g., glucose metabolism, blood perfusion) and convey more information than just the distribution of radioactivity in an organ.
Qualitative vs. Quantitative Image Analysis
Image analysis approaches span the spectrum from what we would call "Qualitative" to what we would call "Quantitative." This section of the paper focuses on quantitative approaches to image analysis.Approaches to Quantitative Image Analysis
Listed below are PET image analysis approaches, which, from top to bottom, incorporate increasing degrees of quantitation. The greatest degree of quantitation involves modeling of the PET tracer in the tissue.
1. Radioactivity Image
With the "Radioactivity images" approach, "what you see is what you get." Immediately following reconstruction, PET images are in units of counts per minute per pixel (or counts per second per pixel). However, the images are typically calibrated in units of counts per minute per milliliter of tissue. This calibration can be performed by scanning a tracer-filled cylinder of known activity and volume. The PET images are then displayed on a computer display, with each pixel assigned a display color according to a color look-up table.
2. Mean Value in Region of Interest
In the "Mean value in region of interest" approach, one uses a computer to draw a region (ROI) around a contiguous set of pixels in the PET image. The computer then computes the mean value of the pixels in the ROI. In the above image, the left striatum is outlined.
3. Time-Activity Curve for ROI
The "Time-activity curve for ROI" approach generates a plot of the mean radioactivity value in an ROI across a sequence of PET images (i.e., across time). Each data point corresponds to the mean pixel value in a common region of interest at a given time.
4. Normalized ROI Curve
The "Normalized ROI curve" approach involves plotting, across time, the ratio of one ROI's time-activity curve to another ROI's time-activity curve.
5. Tracer Modeling of ROI Curve
In the "Tracer modeling of ROI curve" approach, one fits a mathematical model to an ROI time-activity curve, based on a known input function (e.g., from well-counted arterial plasma samples taken during the PET study). The fitting produces estimates of the model's parameters. These parameters might be rate constants, blood flow, or receptor density.
Criteria for Quantitative Image Analysis
Each of the five listed approaches to quantitative image analysis can be described according to four criteria. A sixth approach to quantitative image analysis is parametric imaging. Briefly, the value of each pixel of a parametric image represents the model estimate of the parameter of interest at that location in the image. To generate such an image, the tracer model is applied individually to each pixel of the radioactivity image.
(i) Speed:
• Radioactivity Image: "Radioactivity image" is the fastest among the five analysis approaches. This is what the reconstruction (+ calibration) process gives us.
• Mean Value in Region of Interest: "Mean value in region of interest" requires a moderate amount of time. This involves drawing, with the aid of a mouse, trackball, or joystick, a region around a structure of interest in a PET image and then commanding the computer to compute the mean of the values of the pixels within the region of interest (ROI).
• Time-Activity Curve for ROI: "Time-activity curve for ROI" requires only slightly more time than "Mean value in region of interest." It involves commanding the computer to apply ROI analysis to a temporally sequential set of PET images and to plot that sequence of mean values over the time intervals during which the PET images were obtained.
• Normalized ROI Curve: "Normalized ROI curve" requires only slightly more time than "Time-activity curve for ROI." It involves plotting the ratio of the structure-of- interest's ROI curve to a "normalizing" structure's ROI curve.
• Tracer Modeling of ROI Curve: "Tracer modeling of ROI curve" is the slowest among the five analysis approaches. Based on a plasma curve (which acts as the model input function), the ROI time-activity curve is fitted by a tracer model to estimate parameters that are biochemically or physiologically meaningful.
(ii) Precision:
• Radioactivity Image: Among the approaches, "Radioactivity image" suffers from the poorest precision. Given identical subject and experimental conditions, the value of a given pixel in a given plane at a given scan will vary from study to study due to the Poisson nature of radioactive decay. The other analysis approaches use more information, resulting in relatively better precision.
• Mean Value in Region of Interest: "Mean value in region of interest," relative to the other analysis approaches, enjoys fair precision. Statistical theory demonstrates that the mean from repeated samples of a population (e.g., of pixels in a region) has less variance (i.e., greater precision) than does the sample operator itself (e.g., of individual pixels in a reconstructed image).
• Time-Activity Curve for ROI: "Time-activity curve for ROI" has fair precision, due to the fair precision of "Mean value in region of interest," from which it is derived.
• Normalized ROI Curve: "Normalized ROI curve" has fair precision, due to the fair precision of "Time-activity curve for ROI," from which it is derived.
• Tracer Modeling of ROI Curve: "Tracer modeling of ROI curve" has the best precision among the five analysis approaches. For this approach, precision refers to the reproducibility of the parameter estimates. Because these estimates derive from the ROI curve and from the plasma curve, one could think of this approach as using the most information from a study.
(iii) Comparability with Other PET Studies:
• Radioactivity Image: Using the "Radioactivity image" approach, it is difficult to compare one study with other PET studies. The only comparability available is of a "global" nature one can compare the overall pattern (of low-to-high pixel values) of one PET image to that of one or more other PET images (e.g., to decide whether the pattern matches a pattern that is characteristic of a disease).
• Mean Value in Region of Interest: Using the "Mean value in region of interest" approach, it is impossible to compare one study with other PET studies. The inherent variability in a PET system prevents this.
• Time-Activity Curve for ROI: Using the "Time-activity curve" approach, one can crudely compare one study with another PET study. Although absolute values of curves from two PET studies cannot be compared, shapes of curves can be compared.
• Normalized ROI Curve: The "Normalized ROI curve" approach provides for reasonable comparability of one PET study with another such study. A normalized ROI curve is the plot of a ratio across time, and biological ratios have been found to be reasonably comparable throughout biochemistry and physiology.
• Tracer Modeling of ROI Curve: The "Tracer modeling of ROI curve" approach allows for excellent comparability among PET studies. With this approach, what is being compared are the estimates of the model parameters. Assuming that the model is sensitive & specific for the PET tracer, the parameter estimates are easily compared from study to study.
Conclusion:
A conventional "X-ray" is taken by firing X-rays through a person and onto a film. This "shadow" image shows some structures in the body, such as cartilage and bone. A CT scanner uses fine streams of X-rays. By firing them through the body from several directions, the CT scanner is able to build up a composite picture of anatomical details within a "slice" through the person. Magnetic Resonance Imaging (MRI) does much the same thing, but using magnetic and radiowave fields. In contrast, the PET scanner utilizes radiation emitted from the patient to develop images. The single photon imaging still suffers from problems of poor sensitivity and poor quantitative accuracy. Positron emission tomography has inherent advantages that avoid these shortcomings. Attenuation correction is easily accomplished; positron-emitting isotopes of carbon, nitrogen, oxygen, and fluorine occur naturally in many compounds of biological interest, and can therefore be readily incorporated into a wide variety of useful radio-pharmaceuticals; and collimation is done electronically, so no collimator is required, leading to relatively high sensitivity. The major problem with PET is its cost. The short half-life of most positron emitting isotopes requires an on-site cyclotron, and the scanners themselves are significantly more expensive than single-photon cameras. Nevertheless, PET is widely used in research studies and is finding growing clinical acceptance, primarily for the diagnosis and staging of cancer
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