From WolfWikis

Positron Emission Tomography (PET)

Introduction and History

20 year old brain showing normal levels of FDG metabolic activity [8]

Introduction

Positron emission tomography (PET) is an imaging system that uses the photons produced from positron-electron collisions to measure the movement of decaying radioactive species throughout the body. Important nucleotides include ¹¹C, ¹³N, ¹⁵O, and ¹⁸F, which can be incorporated into other organic molecules such as glucose, water, carbon dioxide, and ammonia. While magnetic resonance imaging (MRI) has been widely used for a number of years, PET has only become more commonplace since the 1990s as it became clear that PET offered complementary information to that obtained in an MRI. X-ray computed tomography (CT), magnetic resonance imaging, and positron emission tomography are now widely used together to provide a comprehensive look at the body’s functions without surgery. MRI can identify the type of tissue or the blood flow. CT produces a 3D image of 2D x-ray scans, providing an inside look at the body without surgery. PET provides insight into the biological processes. Often PET and CT are used in conjunction with each other to create a 3D image with information about biological processes. [1]

Importance

PET, CT, and MRI are three techniques that are frequently used in cancer diagnosis and monitoring of tumor growth. Previously, upon detection of a tumor, immediate efforts were made to remove the tumor with surgery or diagnose the tumor with biopsy. With the improvement of non invasive analytical equipment, essential information can be obtained without surgery. While first used for brain tumors, PET is now used extensively in all types of oncology, as well as pediatrics, and even with infectious diseases like HIV. PET also has a place in preventative medicine in drug development and in gene therapy. PET’s unique advantage is its specificity of probing a particular process with the type of radioactive probe selected. [1]

Detection of brain tumors, whether benign or cancerous, is complex. In the U.S. during the year 2000, about 16,500 malignant tumors in the central nervous system were detected and lead to 13,000 deaths. Patients 19 years of age or less have a 5 year survival rate of 65%, while patients 44 years of age of less have a 5 year survival rate of 58.7%. Patients 65 years of age or older have an extremely low survival rate of less than 6.5%. Clearly, any more information determined in a less expensive, non evasive manner is of extreme importance. 2- [¹⁸ F]-fluoro-2-deoxy-D-glucose (FDG) PET can provide information about metabolic activity that gives diagnostic information about tumor grade, prognosis, and tumor reoccurrence because the high level of glucose metabolized in the brain. [1]

History

First clinical positron imaging device. Drs. Brownell (left) and Aronow are shown with scanner (1953). [7]

Discovery of Positrons

The positron, an essential component of positron-emission tomography, was first predicted in 1928 by Paul Dirac. Dirac predicted a particle with electron mass and positive charge. Carl Anderson confirmed Dirac’s theoretical particle in 1932 during cosmic ray research in cloud chambers. This lead to discovering that when positrons interact with matter, the positron and electron annihilate to form two protons that are emitted very close to 180 degrees. This positron-electron pair characteristic – two photons emitted in opposite directions – was exploited to create PET scans. [1]

Creation of Positron Imaging Device

The first positron imaging device was created in 1950 by William Sweet and Gordon L. Brownell at the Massachusetts General Hospital. The positron scanner included two sodium iodide detectors that used translational movement to form a 2D image. Coincidence scans are images created from photons produced in the same positron-electron collision. Unbalance scans are a result of nonuniformity in detection and are sensitive to the presence of a tumor. Addition detectors were added later for a more effective 3D image. [7]

A significant improvement in both CT and PET imaging was the work of David Chesler from Massachusetts General Hospital. He invented filtered back projection, a technique to produce images from the projection of the light. It produced three types of images: an emission image, a transmission image, and an absorption-corrected image. [7]

The next improvement in PET instrumentation was the creation of a ring like PET device, credited to James Robertson and Z.H.Cho. High resolution PET images were obtained without movement. The model of PET used today is a combined CT/PET scan in a ring like shape. [7]

Discovery of Useful Radioactive Nucleotides

One of the important factors in the usefulness of PET has been the discovery of radioactive nucleotides with long half lives. Some of the very first studies were respiratory studies using ¹⁵O which has a half life of only 122 seconds. Some steady state techniques were developed to make the radioactive oxygen more useful. FDG, the nucleotide used widely in brain research, has a half life of 109.7 minutes, or a little less than two hours. This still requires that a cyclotron capable of producing the nucleotides is located in close proximity to the the PET device, but was a great improvement over previously used nucleotides. Another important nucleotide is the ¹¹C nucleotide, with a half life of 20.38 minutes. These nucleotides and others have been incorporated into molecules engineered for the specific biological process of interest. [1]

Current Applications

PET is a test that gives an image that leads to important information. This test is a leading diagnostic tool for oncology, cardiology, and neurology as well as other applications.

Oncology

When attempting to diagnose a patient with cancer the patient is given a glucose solution which contains a radioactive tracer that can be detected by the PET scanner. The reason that a glucose solution is used is that cancer tissue uses glucose as a food much more than other types of tissues. Due to this the cancer cells absorb much more of the radioactive tracer than other parts of the body. It has been found that PET scans are more beneficial when used with a CT scan. This is because the CT scan gives accurate placement of the cancer within the patients anatomy. The reason a PET scan is used over other types of scans for oncology is that most scans, such as X-rays, detect changes in anatomy, while PET scans detect changes in biochemistry. [2]

Cardiology

When using a PET scan to diagnose heart disease the tracer Rubidium-82 is most often used. This tracer is transported to the heart by injecting it into a vein in the arm. A PET camera then constructs an image of the heart. From this image the health of the vessels, heart muscle and surrounding tissue can be determined. In cardiology the most common use is to identify heart muscle with damage that could be reversed by fixing blocked arteries. This information then allows the physician to determine which steps to take in healing the heart. [3]

Neurology

Since PET scans detect changes in biochemistry within certain parts of the body it is able to show which parts of the brain are working differently than expected. An example of this being useful is for epilepsy patients a surgery is done to remove part of the brain. The PET scan becomes helpful because it shows the exact part of the brain that is causing the epilepsy. PET has also been used in diagnosing Alzheimer's and Parkinson's patients as the images can show which parts of the brain are working improperly.[4]

Physics

Beta Decay - Violating Conservation Laws?

Expected Energy Spectra[12]

Upon its discovery, β-decay created an immediate vexation for the founding fathers of quantum mechanics as it appeared to break several conservation laws. In formulas 1&2 the initial understanding of β^- and β⁺ are shown. The essential phenomena is the flipping of a proton to a neutron, or vice versa, and the release of a charged particle, electron/positron. As shown in the image to the right, the observed spectra of the electron/positrons created in β-decay was vastly different than the expected spectrum. As the nuclear transition was the same for each decay, such a broad energy spectrum meant that either something was missing, or that conservation of energy was violated[12].

Formula 1: β-decay(-) ¹⁴C = ¹⁴N+e^-

Formula 2: β-decay(+) ⁿ_zX = ⁿ_z-1Y+e⁺

In the above formulas, conservation of angular momentum is also violated through incorrect spin conservation. As discussed in class, the change in spin is required to be an integer value. In Formula 1, as shown below, a non integer change in spin of 1.5 is observed.

Spin Values(Formula 1): 0 => 1 + 1/2

Δ Spin 1 = 1 1/2

Quantum physicists continued to investigate β- decay because of these violations of fundamental principles.

While the issues with angular momentum were not apparent at first, the issue of conservation of energy appeared almost instantaneously. Lev Landau, and one of Pauli's assitants, Peierls, published a paper (1931) arguing that electromagnetic fields are impossible to measure in the quantum domain, using the breaking of energy conservation in β-decay as further evidence of the inaccuracy of quantum electromagnetic fields. These results challenged the validity of quantum electrodynamics[10]. Bohr, Heisenberg and Pauli believed that Landau and Peirerls were incorrect and that quantum electrodynamics were possible to experimentally validate.

After the discovery of the neutron in 1930, Heisenberg attempted to simplify the nucleus by introducing the neutron to it. As he wrote to Pauli in 1932[10]

The basic idea is to shift the blame for all principle difficulties onto the neutron [divergent self-evergies too] and to refine quantum mechanics in the nucleus' (Pauli 1985)³

Ultimately, this approach greatly simplified quantum mechanics for the nucleus. However, the problems of energy conservation and angular momentum conservation remained. Further development led to our current understanding which is discussed below.

Line of Nuclear Stability[9]

For nuclei, there is a "line of stability" in terms of the ratio between protons and neutrons[9]. This line initially follows a one to one ratio, then begins to require more and more neutrons to maintain stability. Even in an unstable nucleus, simply ejecting a proton or neutron is a dubiously energy consuming process as the protons and neutrons are still tightly bound in the nucleus by the strong force. As such, the most energy efficient way for a nucleus to stabalize is through use of a weak nuclear force interaction. In it, one of the three quarks in a proton or neutron switches "flavor", ultimately converting a proton into a neutron or vice versa. The resulting formulas are:

Formula 3: β-decay(-) n⁰ = p⁺+e^-+antiNeutrino

Formula 4: β-decay(+) p⁺ = n⁰+e⁺+Neutrino

Spin Values(Formula 3): 1/2 => 1/2 + 1/2 + 1/2

Spin Values(Formula 4): 1/2 => 1/2 + 1/2 + 1/2

The spin changes by an integer value:
Δ Spin 3 = +/- 1

Δ Spin 4 =+/- 1

A neutrino or an antineutrino is neutral particle,a lepton, with spin = 1/2. It has a small but non-zero mass. The neutrino was theorized to explain the difference in energy and angular momentum observed in β-decay. The nuclear decay has the same quantized energy each decay, however, with the neutrino/antineutrino the broad peak of the positron/electron energy is allowed as the neutrino/antineutrino carries the remainder of the energy. The change in spin is also able to be 1 or -1, which conserves spin.

As to why β-decay occurs, a nuclei's stability one aspect of stability is the ratio of protons to neutrons. When a nucleus becomes unstable, radiation occurs. In the case of beta decay this occurs through the weak force. By converting a proton into a neutron or vice versa, the nucleus becomes more stable.

Pair Annihilation

Now that we know how beta decay works, lets look at the original predication by Dirac that a positron, a positively charged electron, exists.

This prediction was based on relativistic energy for particles with no kinetic energy

E² = (m c²)²

E = +/- m c²

Therefore at zero kinetic energy, negative energy states are possible. This is a part of the Dirac Sea model, which says that a vacuum is in fact an infinite sea of negative energy electrons. Further, converting the kinetic energy of a photon into mass without violating the conservation of energy is possible. For this to occur and create an electron, another particle of positive charge must be created to satisfy charge conservation.

γ => e^-+e⁺

Illustration of beta decay and pair annihilation[11]

Pair annihilation occurs when a positron and electron are at low enough energy for their opposite charges to pull them together. Upon contact they create two gamma rays, as releasing only one is prohibited by conservation of linear momentum. Both photons have the same energy, and thus frequency. This frequency is constant as shown below.

2 M _e c² = 2 h f

hf=m_ec²=0.511 MeV

The positron typically annihilates < 10mm of the site of its decay. Knowing the energy of the gamma rays, and that they initiate in opposite directions makes the use of Positron Emission Tomography possible.

Modern Physics Phenomena

The description of β-decay in a radioactive nucleotide and the resulting positron-electron pair annihilation are both modern physics phenomena and cannot be understood classically. β-decay produces a positron/electron and a neutrino/antineutrino as a result of electroweak forces within the nucleus. All of these concepts do not exist in classical physics. β-decay and positron-electron pair annihilation are quantum mechanic processes that have been exploited to create an image in the PET scanning process. The practice of medicine benefits greatly from this inventive imaging technique.

Picture and Animation

Person in a PET camera array

The following animation shows Pair Annihilation (Click the link to open in Windows Media Player): [1] (Animation Credit: Shane Di Dona)

Conclusion

PET has a bright future as it continues to be implemented in more hospitals and as more useful radioactive nucleotides continue to be engineered into molecules used in more biological processes. Future development will include more radioactive nucleotides, ideally with longer half lives. The usefulness of already known radioactive nucleotides with expand as these molecules with be applied to additional biological processes. Another future improvement will be building more cyclotrons to produce the necessary radioactive nucleotides so that more communities can have access to PET.

Nuclear medicine has become an expected part of cancer detection and monitoring, as well as a useful tool in biological research. However, PET is a lesser known technique and most people do not know this technology exists, unless through a personal encounter with a PET scan through cancer or some other disease. Access to PET is limited by the need to have a cyclotron close enough to produce radioactive nucleotides, limiting PET to larger and wealthier hospitals. The noninvasive nature of PET makes PET a preferred method to surgery or biopsies, previously the method of choice for cancer detection. Imaging is also less expensive than surgery.

The scientific community previously thought that MRIs surpassed PET in every useful way. However, in the past decade, PET has really developed and come to be accepted in the scientific community. It has the ability to monitor specific biochemistry depending on the molecule used and investigate many different diseases and biological functions because the wide number of molecules that can be created with radioactive components. As PET has risen in prominence and PET scanners and the supporting cyclotrons have spread across the world, more doctors and researchers are able to use, develop and validate the technique. PET is now widely used to detect cancer, determine if a cancer is spreading, determine blood flow to the heart, identify whether open heart surgery is needed, investigate brain tumors and seizures, as well as investigate normal heart and brain function. PET has become an important part of nuclear medicine for both society and the scientific community.

Resources

[2] Positron Emission Tomography: Basic Science and Clinical Practice

[3] Tennesee Oncology. Accessed April 26, 2009.

[4] Emory Healthcare. Accessed April 26, 2009.

[5] Better Health Channel. Accessed April 26 2009.

[6]Tool Box - Listing of Half Lives (Half Life) for Radioactive Elements. Accessed April 26, 2009.

[7] Introduction to PET Physics. Accessed April 4, 2009.

[8] A History of Positron Imaging. Accessed April 4, 2009.

[9] National Institute on Aging. Accessed April 26, 2009.

[9] Thornton, Stephen, and Andrew Rex. Modern Physics for Scientists and Engineers. 3. Belmont CA: Thomson Brooks/Cole, 2006. Print.

[10] Miller, Arthur, and Walter Grant. Early Quantum Electrodynamics: a source book. 1. New York, NY: Cambridge University Press, 1994. Print.

[11] Valk, Peter, Dale Bailey, David Townsend, and Michael Maisey.Positron Emission Tomography: Basic Science and Clinical Practice. 1. London, UK: Springer-Verlag, 2003. Print.

[12] Jeff, Bryan. Introduction to Nuclear Science. 1. Boca Raton, FL: CRC Press: Taylor & Francis Group, 2009. Print.

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