Positron emission tomography (PET) is a nuclear medicine imaging technique that produces a three-dimensional image or map of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer), which is introduced into the body on a biologically active molecule. Images of tracer concentration in 3-dimensional space within the body are then reconstructed by computer analysis. In modern scanners, this reconstruction is often accomplished with the aid of a CT X-ray scan performed on the patient during the same session, in the same machine.
If the biologically active molecule chosen for PET is FDG ([18F]-fluorodeoxyglucose), an analog of glucose, the concentrations of tracer imaged then give tissue metabolic activity, in terms of regional glucose uptake. This tracer is used in the most common type of PET scan, but other tracer molecules are also used in PET to image the tissue concentration of many other types of molecules of interest.
The concept of emission and transmission tomography was introduced by David Kuhl and Roy Edwards in the late 1950s. Their work later led to the design and construction of several tomographic instruments at the University of Pennsylvania. Tomographic imaging techniques were further developed by Michel Ter-Pogossian, Michael E. Phelps, and coworkers at the Washington University School of Medicine.
Beginning in the 1950s, the work of Gordon Brownell, Charles Burnham, and their colleagues at the Massachusetts General Hospital contributed significantly to the development of PET technology and included the first demonstration of annihilation radiation for medical imaging. Their innovations, including the use of light pipes, and volumetric analysis have been important in the deployment of PET imaging.
In the 1970s, Tatsuo Ido at the Brookhaven National Laboratory was the first to describe the synthesis of 18F-FDG ([18F]-fluorodeoxyglucose), the most commonly used PET scanning isotope carrier. The compound was first administered to two normal human volunteers by Abass Alavi in August 1976 at the University of Pennsylvania. Brain images obtained with an ordinary (non-PET) nuclear scanner demonstrated the concentration of FDG in that organ. Later, the substance was used in dedicated positron tomographic scanners, to yield the modern procedure.
To conduct the scan, a short-lived radioactive tracer isotope, is injected into the living subject (usually into blood circulation). The tracer is chemically incorporated into a biologically active molecule, and eventually decays, emitting a positron. There is a waiting period while the active molecule becomes concentrated in tissues of interest; then the research subject or patient is placed in the imaging scanner. The molecule most commonly used for this purpose is fluorodeoxyglucose (FDG), a sugar, for which the waiting period is typically an hour.
As the radioisotope undergoes positron emission decay (also known as positive beta decay), it emits a positron, the antimatter counterpart of an electron. After traveling up to a few millimeters the positron encounters and annihilates with an electron, producing a pair of annihilation (gamma) photons moving in opposite directions. These are detected when they reach a scintillator material in the scanning device, creating a burst of light which is detected by photomultiplier tubes or silicon avalanche photodiodes (Si APD). The technique depends on simultaneous or coincident detection of the pair of photons; photons which do not arrive in pairs (that is, within a timing window of few nanoseconds) are ignored.
The most significant fraction of electron-positron decays result in two 511 keV gamma photons being emitted at almost 180 degrees to each other; hence it is possible to localize their source along a straight line of coincidence (also called formally the line of response or LOR). In practice the LOR has a finite width as the emitted photons are not exactly 180 degrees apart. If the recovery time of detectors is in the picosecond range rather than the 10's of nanosecond range, it is possible to localize the event to a segment of a cord, whose length is determined by the detector timing resolution. As the timing resolution improves, the signal-to-noise ratio (SNR) of the image will improve, requiring less events to achieve the same image quality. This technology is not yet common, but it is available on some new systems.
More commonly, a technique much like the reconstruction of computed tomography (CT) and single photon emission computed tomography (SPECT) data is used, although the data set collected in PET is much poorer than CT, so reconstruction techniques are more difficult (see Image reconstruction of PET).
Using statistics collected from tens-of-thousands of coincidence events, a set of simultaneous equations for the total activity of each parcel of tissue along many LORs can be solved by a number of techniques, and thus a map of radioactivities as a function of location for parcels or bits of tissue (also called voxels), may be constructed and plotted. The resulting map shows the tissues in which the molecular probe has become concentrated, and can be interpreted by a nuclear medicine physician or radiologist in the context of the patient's diagnosis and treatment plan.
PET scans are increasingly read alongside CT or magnetic resonance imaging (MRI) scans, the combination ("co-registration") giving both anatomic and metabolic information (that is, what the structure is, and what it is doing biochemically). Because PET imaging is most useful in combination with anatomical imaging, such as CT, modern PET scanners are now available with integrated high-end multi-detector-row CT scanners. Because the two scans can be performed in immediate sequence during the same session, with the patient not changing position between the two types of scans, the two sets of images are more-precisely registered, so that areas of abnormality on the PET imaging can be more perfectly correlated with anatomy on the CT images. This is very useful in showing detailed views of moving organs or structures with higher amounts of anatomical variation, such as are more likely to occur outside the brain.
Radionuclides used in PET scanning are typically isotopes with short half lives such as carbon-11 (~20 min), nitrogen-13 (~10 min), oxygen-15 (~2 min), and fluorine-18 (~110 min). These radionuclides are incorporated either into compounds normally used by the body such as glucose (or glucose analogues), water or ammonia, or into molecules that bind to receptors or other sites of drug action. Such labelled compounds are known as radiotracers. It is important to recognize that PET technology can be used to trace the biologic pathway of any compound in living humans (and many other species as well), provided it can be radiolabeled with a PET isotope. Thus, the specific processes that can be probed with PET are virtually limitless, and radiotracers for new target molecules and processes are being synthesized all the time; as of this writing there are already dozens in clinical use and hundreds applied in research. Due to the short half lives of most radioisotopes, the radiotracers must be produced using a cyclotron and radiochemistry laboratory that are in close proximity to the PET imaging facility. The half life of fluorine-18 is long enough such that fluorine-18 labeled radiotracers can be manufactured commercially at an offsite location.
The minimization of radiation dose to the subject is an attractive feature of the use of short-lived radionuclides. Besides its established role as a diagnostic technique, PET has an expanding role as a method to assess the response to therapy, in particular, cancer therapy, where the risk to the patient from lack of knowledge about disease progress is much greater than the risk from the test radiation.
Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to produce the short-lived radionuclides for PET scanning and the need for specially adapted on-site chemical synthesis apparatus to produce the radiopharmaceuticals. Few hospitals and universities are capable of maintaining such systems, and most clinical PET is supported by third-party suppliers of radiotracers which can supply many sites simultaneously. This limitation restricts clinical PET primarily to the use of tracers labeled with F-18, which has a half life of 110 minutes and can be transported a reasonable distance before use, or to rubidium-82, which can be created in a portable generator and is used for myocardial perfusion studies. Nevertheless, in recent years a few on-site cyclotrons with integrated shielding and hot labs have begun to accompany PET units to remote hospitals. The presence of the small on-site cyclotron promises to expand in the future as the cyclotrons shrink in response to the high cost of isotope transportation to remote PET machines 
Because the half-life of F-18 is about two hours, the prepared dose of a radiopharmaceutical bearing this radionuclide will undergo multiple half-lives of decay during the working day. This necessitates frequent recalibration of the remaining dose (determination of activity per unit volume) and careful planning with respect to patient scheduling.
The raw data collected by a PET scanner are a list of 'coincidence events' representing near-simultaneous detection of annihilation photons by a pair of detectors. Each coincidence event represents a line in space connecting the two detectors along which the positron emission occurred.
Coincidence events can be grouped into projections images, called sinograms. The sinograms are sorted by the angle of each view and tilt, the latter in 3D case images. The sinogram images are analogous to the projections captured by computed tomography (CT) scanners, and can be reconstructed in a similar way. However, the statistics of the data is much worse than those obtained through transmission tomography. A normal PET data set has millions of counts for the whole acquisition, while the CT can reach a few billion counts. As such, PET data suffer from scatter and random events much more dramatically than CT data does.
In practice, considerable pre-processing of the data is required—correction for random coincidences, estimation and subtraction of scattered photons, detector dead-time correction (after the detection of a photon, the detector must "cool down" again) and detector-sensitivity correction (for both inherent detector sensitivity and changes in sensitivity due to angle of incidence).
Filtered back projection (FBP) has been frequently used to reconstruct images from the projections. This algorithm has the advantage of being simple while having a low requirement for computing resources. However, shot noise in the raw data is prominent in the reconstructed images and areas of high tracer uptake tend to form streaks across the image.
Iterative expectation-maximization algorithms are now the preferred method of reconstruction. The advantage is a better noise profile and resistance to the streak artifacts common with FBP, but the disadvantage is higher computer resource requirements.
Attenuation correction: As different LORs must traverse different thicknesses of tissue, the photons are attenuated differentially. The result is that structures deep in the body are reconstructed as having falsely low tracer uptake. Contemporary scanners can estimate attenuation using integrated x-ray CT equipment, however earlier equipment offered a crude form of CT using a gamma ray (positron emitting) source and the PET detectors.
While attenuation corrected images are generally more faithful representations, the correction process is itself susceptible to significant artifacts. As a result, both corrected and uncorrected images are always reconstructed and read together.
2D/3D reconstruction: Early PET scanners had only a single ring of detectors, hence the acquisition of data and subsequent reconstruction was restricted to a single transverse plane. More modern scanners now include multiple rings, essentially forming a cylinder of detectors.
There are two approaches to reconstructing data from such a scanner: 1) treat each ring as a separate entity, so that only coincidences within a ring are detected, the image from each ring can then be reconstructed individually (2D reconstruction), or 2) allow coincidences to be detected between rings as well as within rings, then reconstruct the entire volume together (3D).
3D techniques have better sensitivity (because more coincidences are detected and used) and therefore less noise, but are more sensitive to the effects of scatter and random coincidences, as well as requiring correspondingly greater computer resources.
PET is both a medical and research tool. It is used heavily in clinical oncology (medical imaging of tumors and the search for metastases), and for clinical diagnosis of certain diffuse brain diseases such as those causing various types of dementias. PET is also an important research tool to map normal human brain and heart function.
PET is also used in pre-clinical studies using animals, where it allows repeated investigations into the same subjects. This is particularly valuable in cancer research, as it results in an increase in the statistical quality of the data (subjects can act as their own control) and substantially reduces the numbers of animals required for a given study.
Alternative methods of scanning include x-ray computed tomography (CT), magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI), ultrasound, and single photon emission computed tomography (SPECT).
While some imaging scans such as CT and MRI isolate organic anatomic changes in the body, PET and SPECT are capable of detecting areas of molecular biology detail (even prior to anatomic change). PET scanning does this using radiolabelled molecular probes that have different rates of uptake depending on the type and function of tissue involved. Changing of regional blood flow in various anatomic structures (as a measure of the injected positron emitter) can be visualized and relatively quantified with a PET scan.
PET imaging is best performed using a dedicated PET scanner. However, it is possible to acquire PET images using a conventional dual-head gamma camera fitted with a coincidence detector. The quality of gamma-camera PET is considerably lower, and acquisition is slower. However, for institutions with low demand for PET, this may allow on-site imaging, instead of referring patients to another center, or relying on a visit by a mobile scanner.
PET is a valuable technique for some diseases and disorders, because it is possible to target the radio-chemicals used for particular bodily functions.
PET scanning is non-invasive, but it does involve exposure to ionizing radiation. The total dose of radiation is small, however, usually around 7 mSv. This can be compared to 2.2 mSv average annual background radiation in the UK, 0.02 mSv for a chest x-ray, up to 8 mSv for a CT scan of the chest, 2-6 mSv per annum for aircrew. Patients with small children may be advised to limit proximity to them for several hours following the completion of the test.
All links retrieved May 26, 2015.
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