Molecular imaging

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Molecular_imaging 

 

Molecular imaging is a field of medical imaging that focuses on imaging molecules of medical interest within living patients. This is in contrast to conventional methods for obtaining molecular information from preserved tissue samples, such as histology. Molecules of interest may be either ones produced naturally by the body, or synthetic molecules produced in a laboratory and injected into a patient by a doctor. The most common example of molecular imaging used clinically today is to inject a contrast agent (e.g., a microbubble, metal ion, or radioactive isotope) into a patient's bloodstream and to use an imaging modality (e.g., ultrasound, MRI, CT, PET) to track its movement in the body. Molecular imaging originated from the field of radiology from a need to better understand fundamental molecular processes inside organisms in a noninvasive manner.

The ultimate goal of molecular imaging is to be able to noninvasively monitor all of the biochemical processes occurring inside an organism in real time. Current research in molecular imaging involves cellular/molecular biology, chemistry, and medical physics, and is focused on: 1) developing imaging methods to detect previously undetectable types of molecules, 2) expanding the number and types of contrast agents available, and 3) developing functional contrast agents that provide information about the various activities that cells and tissues perform in both health and disease.

Overview

Molecular imaging emerged in the mid twentieth century as a discipline at the intersection of molecular biology and in vivo imaging. It enables the visualisation of the cellular function and the follow-up of the molecular process in living organisms without perturbing them. The multiple and numerous potentialities of this field are applicable to the diagnosis of diseases such as cancer, and neurological and cardiovascular diseases. This technique also contributes to improving the treatment of these disorders by optimizing the pre-clinical and clinical tests of new medication. They are also expected to have a major economic impact due to earlier and more precise diagnosis. Molecular and Functional Imaging has taken on a new direction since the description of the human genome. New paths in fundamental research, as well as in applied and industrial research, render the task of scientists more complex and increase the demands on them. Therefore, a tailor-made teaching program is in order.

Molecular imaging differs from traditional imaging in that probes known as biomarkers are used to help image particular targets or pathways. Biomarkers interact chemically with their surroundings and in turn alter the image according to molecular changes occurring within the area of interest. This process is markedly different from previous methods of imaging which primarily imaged differences in qualities such as density or water content. This ability to image fine molecular changes opens up an incredible number of exciting possibilities for medical application, including early detection and treatment of disease and basic pharmaceutical development. Furthermore, molecular imaging allows for quantitative tests, imparting a greater degree of objectivity to the study of these areas. One emerging technology is MALDI molecular imaging based on mass spectrometry.

Many areas of research are being conducted in the field of molecular imaging. Much research is currently centered on detecting what is known as a predisease state or molecular states that occur before typical symptoms of a disease are detected. Other important veins of research are the imaging of gene expression and the development of novel biomarkers. Organizations such as the SNMMI Center for Molecular Imaging Innovation and Translation (CMIIT) have formed to support research in this field. In Europe, other "networks of excellence" such as DiMI (Diagnostics in Molecular Imaging) or EMIL (European Molecular Imaging Laboratories) work on this new science, integrating activities and research in the field. In this way, a European Master Programme "EMMI" is being set up to train a new generation of professionals in molecular imaging.

Recently the term molecular imaging has been applied to a variety of microscopy and nanoscopy techniques including live-cell microscopy, Total Internal Reflection Fluorescence (TIRF)-microscopy, STimulated Emission Depletion (STED)-nanoscopy and Atomic Force Microscopy (AFM) as here images of molecules are the readout.

Imaging modalities

There are many different modalities that can be used for noninvasive molecular imaging. Each have their different strengths and weaknesses and some are more adept at imaging multiple targets than others.

Magnetic resonance imaging

Molecular MRI of a mouse brain presenting acute inflammation in the right hemisphere. Whereas unenhanced MRI failed to reveal any difference between right en left hemispheres, injection of a contrast-agent targeted to inflamed vessels allows to reveal inflammation specifically in the right hemisphere.

Main article: Magnetic resonance imaging

MRI has the advantages of having very high spatial resolution and is very adept at morphological imaging and functional imaging. MRI does have several disadvantages though. First, MRI has a sensitivity of around 10⁻³ mol/L to 10⁻⁵ mol/L which, compared to other types of imaging, can be very limiting. This problem stems from the fact that the difference between atoms in the high energy state and the low energy state is very small. For example, at 1.5 Tesla, a typical field strength for clinical MRI, the difference between high and low energy states is approximately 9 molecules per 2 million. Improvements to increase MR sensitivity include increasing magnetic field strength, and hyperpolarization via optical pumping, dynamic nuclear polarization or parahydrogen induced polarization. There are also a variety of signal amplification schemes based on chemical exchange that increase sensitivity.

To achieve molecular imaging of disease biomarkers using MRI, targeted MRI contrast agents with high specificity and high relaxivity (sensitivity) are required. To date, many studies have been devoted to developing targeted-MRI contrast agents to achieve molecular imaging by MRI. Commonly, peptides, antibodies, or small ligands, and small protein domains, such as HER-2 affibodies, have been applied to achieve targeting. To enhance the sensitivity of the contrast agents, these targeting moieties are usually linked to high payload MRI contrast agents or MRI contrast agents with high relaxivities. In particular, the recent development of micron-sized particles of iron oxide (MPIO) allowed to reach unprecedented levels of sensitivity to detect proteins expressed by arteries and veins.

Optical imaging

Main article: Optical imaging

Imaging of engineered E. coli Nissle 1917 in the mouse gut

There are a number of approaches used for optical imaging. The various methods depend upon fluorescence, bioluminescence, absorption or reflectance as the source of contrast.

Optical imaging's most valuable attribute is that it and ultrasound do not have strong safety concerns like the other medical imaging modalities.

The downside of optical imaging is the lack of penetration depth, especially when working at visible wavelengths. Depth of penetration is related to the absorption and scattering of light, which is primarily a function of the wavelength of the excitation source. Light is absorbed by endogenous chromophores found in living tissue (e.g. hemoglobin, melanin, and lipids). In general, light absorption and scattering decreases with increasing wavelength. Below ~700 nm (e.g. visible wavelengths), these effects result in shallow penetration depths of only a few millimeters. Thus, in the visible region of the spectrum, only superficial assessment of tissue features is possible. Above 900 nm, water absorption can interfere with signal-to-background ratio. Because the absorption coefficient of tissue is considerably lower in the near infrared (NIR) region (700-900 nm), light can penetrate more deeply, to depths of several centimeters.

Near Infrared imaging

Fluorescent probes and labels are an important tool for optical imaging. Some researchers have applied NIR imaging in rat model of acute myocardial infarction (AMI), using a peptide probe that can binds to apoptotic and necrotic cells. A number of near-infrared (NIR) fluorophores have been employed for in vivo imaging, including Kodak X-SIGHT Dyes and Conjugates, Pz 247, DyLight 750 and 800 Fluors, Cy 5.5 and 7 Fluors, Alexa Fluor 680 and 750 Dyes, IRDye 680 and 800CW Fluors. Quantum dots, with their photostability and bright emissions, have generated a great deal of interest; however, their size precludes efficient clearance from the circulatory and renal systems while exhibiting long-term toxicity.

Several studies have demonstrated the use of infrared dye-labeled probes in optical imaging.

1. In a comparison of gamma scintigraphy and NIR imaging, a cyclopentapeptide dual-labeled with ¹¹¹
   In and an NIR fluorophore was used to image αvβ3-integrin positive melanoma xenografts.
2. Near-infrared labeled RGD targeting αvβ3-integrin has been used in numerous studies to target a variety of cancers.
3. An NIR fluorophore has been conjugated to epidermal growth factor (EGF) for imaging of tumor progression.
4. An NIR fluorophore was compared to Cy5.5, suggesting that longer-wavelength dyes may produce more effective targeting agents for optical imaging.
5. Pamidronate has been labeled with an NIR fluorophore and used as a bone imaging agent to detect osteoblastic activity in a living animal.
6. An NIR fluorophore-labeled GPI, a potent inhibitor of PSMA (prostate specific membrane antigen).
7. Use of human serum albumin labeled with an NIR fluorophore as a tracking agent for mapping of sentinel lymph nodes.
8. 2-Deoxy-D-glucose labeled with an NIR fluorophore.

It is important to note that addition of an NIR probe to any vector can alter the vector's biocompatibility and biodistribution. Therefore, it can not be unequivocally assumed that the conjugated vector will behave similarly to the native form.

Single photon emission computed tomography

Main article: Single photon emission computed tomography

SPECT image (bone tracer) of a mouse MIP

The development of computed tomography in the 1970s allowed mapping of the distribution of the radioisotopes in the organ or tissue, and led to the technique now called single photon emission computed tomography (SPECT).

The imaging agent used in SPECT emits gamma rays, as opposed to the positron emitters (such as ¹⁸
F) used in PET. There are a range of radiotracers (such as ^99m
Tc, ¹¹¹
In, ¹²³
I, ²⁰¹
Tl) that can be used, depending on the specific application.

Xenon (¹³³
Xe) gas is one such radiotracer. It has been shown to be valuable for diagnostic inhalation studies for the evaluation of pulmonary function; for imaging the lungs; and may also be used to assess rCBF. Detection of this gas occurs via a gamma camera—which is a scintillation detector consisting of a collimator, a NaI crystal, and a set of photomultiplier tubes.

By rotating the gamma camera around the patient, a three-dimensional image of the distribution of the radiotracer can be obtained by employing filtered back projection or other tomographic techniques. The radioisotopes used in SPECT have relatively long half lives (a few hours to a few days) making them easy to produce and relatively cheap. This represents the major advantage of SPECT as a molecular imaging technique, since it is significantly cheaper than either PET or fMRI. However it lacks good spatial (i.e., where exactly the particle is) or temporal (i.e., did the contrast agent signal happen at this millisecond, or that millisecond) resolution. Additionally, due to the radioactivity of the contrast agent, there are safety aspects concerning the administration of radioisotopes to the subject, especially for serial studies.

Positron emission tomography

Main article: Positron emission tomography

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Imaging joint inflammation in an arthritic mouse using positron emission tomography.

 

PET, MRI, and overlaid images of a human brain.

Positron emission tomography (PET) is a nuclear medicine imaging technique which produces a three-dimensional image or picture of functional processes in the body. The theory behind PET is simple enough. First a molecule is tagged with a positron emitting isotope. These positrons annihilate with nearby electrons, emitting two 511 keV photons, directed 180 degrees apart in opposite directions. These photons are then detected by the scanner, which can estimate the density of positron annihilations in a specific area. When enough interactions and annihilations have occurred, the density of the original molecule may be measured in that area. Typical isotopes include ¹¹
C, ¹³
N, ¹⁵
O, ¹⁸
F, ⁶⁴
Cu, ⁶²
Cu, ¹²⁴
I, ⁷⁶
Br, ⁸²
Rb, ⁸⁹
Zr and ⁶⁸
Ga, with ¹⁸
F being the most clinically utilized. One of the major disadvantages of PET is that most of the probes must be made with a cyclotron. Most of these probes also have a half life measured in hours, forcing the cyclotron to be on site. These factors can make PET prohibitively expensive. PET imaging does have many advantages though. First and foremost is its sensitivity: a typical PET scanner can detect between 10⁻¹¹ mol/L to 10⁻¹² mol/L concentrations.

Positron emission tomography

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Positron_emission_tomography 

 

Positron emission tomography
Image of a typical positron emission tomography (PET) scanner
ICD-10-PCS	C?3
ICD-9-CM	92.0-92.1
MeSH	D049268
OPS-301 code	3-74
MedlinePlus	003827

Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body. For example, 18F-FDG is commonly used to detect cancer, NaF-F18 is widely used for detecting bone formation, and oxygen-15 is sometimes used to measure blood flow.

PET is a common imaging technique, a medical scintillography technique used in nuclear medicine. A radiopharmaceutical — a radioisotope attached to a drug — is injected into the body as a tracer. Gamma rays are emitted and detected by gamma cameras to form a three-dimensional image, in a similar way that an X-ray image is captured.

PET scanners can incorporate a CT scanner and are known as PET-CT scanners. PET scan images can be reconstructed using a CT scan performed using one scanner during the same session.

One of the disadvantages of a PET scanner is its high initial cost and ongoing operating costs.

Uses

PET/CT-System with 16-slice CT; the ceiling mounted device is an injection pump for CT contrast agent

PET is both a medical and research tool used in pre-clinical and clinical settings. It is used heavily in the imaging of tumors and the search for metastases within the field of clinical oncology, and for the clinical diagnosis of certain diffuse brain diseases such as those causing various types of dementias. PET is a valuable research tool to learn and enhance our knowledge of the normal human brain, heart function, and support drug development. PET is also used in pre-clinical studies using animals. It allows repeated investigations into the same subjects over time, where subjects can act as their own control and substantially reduces the numbers of animals required for a given study. This approach allows research studies to reduce the sample size needed while increasing the statistical quality of its results.

Physiological processes lead to anatomical changes in the body. Since PET is capable of detecting biochemical processes as well as expression of some proteins, PET can provide molecular-level information much before any anatomic changes are visible. PET scanning does this by using radiolabelled molecular probes that have different rates of uptake depending on the type and function of tissue involved. Regional tracer uptake in various anatomic structures can be visualized and relatively quantified in terms of injected positron emitter within a PET scan.

PET imaging is best performed using a dedicated PET scanner. It is also possible to acquire PET images using a conventional dual-head gamma camera fitted with a coincidence detector. The quality of gamma-camera PET imaging is lower, and the scans take longer to acquire. However, this method allows a low-cost on-site solution to institutions with low PET scanning demand. An alternative would be to refer these patients to another center or relying on a visit by a mobile scanner.

Alternative methods of medical imaging include single-photon emission computed tomography (SPECT), x-ray computed tomography (CT), magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI), and ultrasound. SPECT is an imaging technique similar to PET that uses radioligands to detect molecules in the body. SPECT is less expensive and provides inferior image quality than PET.

Oncology

Whole-body PET scan using 18F-FDG. The normal brain and kidneys are labeled, and radioactive urine from breakdown of the FDG is seen in the bladder. In addition, a large metastatic tumor mass from colon cancer is seen in the liver.

PET scanning with the tracer 18F-FDG is widely used in clinical oncology. FDG is a glucose analog that is taken up by glucose-using cells and phosphorylated by hexokinase (whose mitochondrial form is significantly elevated in rapidly growing malignant tumors). Metabolic trapping of the radioactive glucose molecule allows the PET scan to be utilized. The concentrations of imaged FDG tracer indicate tissue metabolic activity as it corresponds to the regional glucose uptake. 18F-FDG is used to explore the possibility of cancer spreading to other body sites (cancer metastasis). These 18F-FDG PET scans for detecting cancer metastasis are the most common in standard medical care (representing 90% of current scans). The same tracer may also be used for the diagnosis of types of dementia. Less often, other radioactive tracers, usually but not always labelled with fluorine-18, are used to image the tissue concentration of different kinds of molecules of interest inside the body.

A typical dose of FDG used in an oncological scan has an effective radiation dose of 7.6 mSv. Because the hydroxy group that is replaced by fluorine-18 to generate FDG is required for the next step in glucose metabolism in all cells, no further reactions occur in FDG. Furthermore, most tissues (with the notable exception of liver and kidneys) cannot remove the phosphate added by hexokinase. This means that FDG is trapped in any cell that takes it up until it decays, since phosphorylated sugars, due to their ionic charge, cannot exit from the cell. This results in intense radiolabeling of tissues with high glucose uptake, such as the normal brain, liver, kidneys, and most cancers, which have a higher glucose uptake than most normal tissue due to the Warburg effect. As a result, FDG-PET can be used for diagnosis, staging, and monitoring treatment of cancers, particularly in Hodgkin lymphoma, non-Hodgkin lymphoma, and lung cancer.

A 2020 review of research on the use of PET for Hodgkin lymphoma found evidence that negative findings in interim PET scans are linked to higher overall survival and progression-free survival; however, the certainty of the available evidence was moderate for survival, and very low for progression-free survival.

A few other isotopes and radiotracers are slowly being introduced into oncology for specific purposes. For example, ¹¹C-labelled metomidate (11C-metomidate) has been used to detect tumors of adrenocortical origin. Also, FDOPA PET/CT (or F-18-DOPA PET/CT) has proven to be a more sensitive alternative to finding and also localizing pheochromocytoma than the MIBG scan.

Neuroimaging

Main article: Brain positron emission tomography

Neurology

PET scan of the human brain

PET imaging with oxygen-15 indirectly measures blood flow to the brain. In this method, increased radioactivity signal indicates increased blood flow which is assumed to correlate with increased brain activity. Because of its 2-minute half-life, ¹⁵O must be piped directly from a medical cyclotron for such uses, which is difficult.

PET imaging with ¹⁸F-FDG takes advantage of the fact that the brain is normally a rapid user of glucose. Standard ¹⁸F-FDG PET of the brain measures regional glucose use and can be used in neuropathological diagnosis.

Brain pathologies such as Alzheimer's disease greatly decrease brain metabolism of both glucose and oxygen in tandem. Therefore ¹⁸F-FDG PET of the brain may also be used to successfully differentiate Alzheimer's disease from other dementing processes, and also to make early diagnoses of Alzheimer's disease. The advantage of ¹⁸F-FDG PET for these uses is its much wider availability. Some ¹⁸F based radioactive tracers used for Alzheimer's include florbetapir, flutemetamol, PiB and florbetaben, which are all used to detect amyloid-beta plaques (a potential biomarker for Alzheimer's) in the brain.

PET imaging with FDG can also be used for localization of seizure focus. A seizure focus will appear as hypometabolic during an interictal scan. Several radiotracers (i.e. radioligands) have been developed for PET that are ligands for specific neuroreceptor subtypes such as [¹¹C] raclopride, [¹⁸F] fallypride and [¹⁸F] desmethoxyfallypride for dopamine D2/D3 receptors, [¹¹C] McN 5652 and [¹¹C] DASB for serotonin transporters, [¹⁸F] Mefway for serotonin 5HT1A receptors, [¹⁸F] Nifene for nicotinic acetylcholine receptors or enzyme substrates (e.g. 6-FDOPA for the AADC enzyme). These agents permit the visualization of neuroreceptor pools in the context of a plurality of neuropsychiatric and neurologic illnesses.

PET may also be used for the diagnosis of hippocampal sclerosis, which causes epilepsy. FDG, and the less common tracers flumazenil and MPPF have been explored for this purpose. If the sclerosis is unilateral (right hippocampus or left hippocampus), ¹⁸F-FDG uptake can be compared with the healthy side. Even if the diagnosis is difficult with MRI, it may be diagnosed with PET.

The development of a number of novel probes for noninvasive, in vivo PET imaging of neuroaggregate in human brain has brought amyloid imaging close to clinical use. The earliest amyloid imaging probes included 2-(1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([¹⁸F]FDDNP) developed at the University of California, Los Angeles and N-methyl-[¹¹C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (termed Pittsburgh compound B) developed at the University of Pittsburgh. These amyloid imaging probes permit the visualization of amyloid plaques in the brains of Alzheimer's patients and could assist clinicians in making a positive clinical diagnosis of AD pre-mortem and aid in the development of novel anti-amyloid therapies. [¹¹C]PMP (N-[¹¹C]methylpiperidin-4-yl propionate) is a novel radiopharmaceutical used in PET imaging to determine the activity of the acetylcholinergic neurotransmitter system by acting as a substrate for acetylcholinesterase. Post-mortem examination of AD patients have shown decreased levels of acetylcholinesterase. [¹¹C]PMP is used to map the acetylcholinesterase activity in the brain, which could allow for pre-mortem diagnoses of AD and help to monitor AD treatments. Avid Radiopharmaceuticals has developed and commercialized a compound called florbetapir that uses the longer-lasting radionuclide fluorine-18 to detect amyloid plaques using PET scans.

Neuropsychology or cognitive neuroscience

To examine links between specific psychological processes or disorders and brain activity.

Psychiatry

Numerous compounds that bind selectively to neuroreceptors of interest in biological psychiatry have been radiolabeled with C-11 or F-18. Radioligands that bind to dopamine receptors (D1, D2 receptor, reuptake transporter), serotonin receptors (5HT1A, 5HT2A, reuptake transporter) opioid receptors (mu and kappa) cholinergic receptors (nicotinic and muscarinic) and other sites have been used successfully in studies with human subjects. Studies have been performed examining the state of these receptors in patients compared to healthy controls in schizophrenia, substance abuse, mood disorders and other psychiatric conditions.

Stereotactic surgery and radiosurgery

PET-image guided surgery facilitates treatment of intracranial tumors, arteriovenous malformations and other surgically treatable conditions.

Cardiology

Main article: Cardiac PET

Cardiology, atherosclerosis and vascular disease study: 18F-FDG PET can help in identifying hibernating myocardium. However, the cost-effectiveness of PET for this role versus SPECT is unclear. 18F-FDG PET imaging of atherosclerosis to detect patients at risk of stroke is also feasible. Also, it can help test the efficacy of novel anti-atherosclerosis therapies.

Infectious diseases

Imaging infections with molecular imaging technologies can improve diagnosis and treatment follow-up. Clinically, PET has been widely used to image bacterial infections using fluorodeoxyglucose (FDG) to identify the infection-associated inflammatory response. Three different PET contrast agents have been developed to image bacterial infections in vivo are [¹⁸F]maltose, [¹⁸F]maltohexaose, and [¹⁸F]2-fluorodeoxysorbitol (FDS). FDS has the added benefit of being able to target only Enterobacteriaceae.

Bio-distribution studies

In pre-clinical trials, a new drug can be radiolabeled and injected into animals. Such scans are referred to as biodistribution studies. The information regarding drug uptake, retention and elimination over time can be obtained quickly and cost-effectively compare to the older technique of killing and dissecting the animals. Commonly, drug occupancy at a purported site of action can be inferred indirectly by competition studies between unlabeled drug and radiolabeled compounds known apriori to bind with specificity to the site. A single radioligand can be used this way to test many potential drug candidates for the same target. A related technique involves scanning with radioligands that compete with an endogenous (naturally occurring) substance at a given receptor to demonstrate that a drug causes the release of the natural substance.

Small animal imaging

A miniature animal PET has been constructed that is small enough for a fully conscious rat to be scanned. This RatCAP (Rat Conscious Animal PET) allows animals to be scanned without the confounding effects of anesthesia. PET scanners designed specifically for imaging rodents, often referred to as microPET, as well as scanners for small primates, are marketed for academic and pharmaceutical research. The scanners are based on microminiature scintillators and amplified avalanche photodiodes (APDs) through a system that uses single-chip silicon photomultipliers.

In 2018 the UC Davis School of Veterinary Medicine became the first veterinary center to employ a small clinical PET-scanner as a pet-PET scan for clinical (rather than research) animal diagnosis. Because of cost as well as the marginal utility of detecting cancer metastases in companion animals (the primary use of this modality), veterinary PET scanning is expected to be rarely available in the immediate future.

Musculo-skeletal imaging

Further information: PET for bone imaging

PET imaging has been used for imaging muscles and bones. 18F-FDG is the most commonly used tracer for imaging muscles, and NaF-F18 is the most widely used tracer for imaging bones.

Muscles

PET is a feasible technique for studying skeletal muscles during exercises like walking. Also, PET can provide muscle activation data about deep-lying muscles (such as the vastus intermedialis and the gluteus minimus) compared to techniques like electromyography, which can be used only on superficial muscles directly under the skin. However, a disadvantage is that PET provides no timing information about muscle activation because it has to be measured after the exercise is completed. This is due to the time it takes for FDG to accumulate in the activated muscles.

Bones

Together with NaF-F18, PET for bone imaging has been in use for 60 years for measuring regional bone metabolism and blood flow using static and dynamic scans. Researchers have recently started using NaF-18 to study bone metastasis as well.

Safety

PET scanning is non-invasive, but it does involve exposure to ionizing radiation.

18F-FDG, which is now the standard radiotracer used for PET neuroimaging and cancer patient management, has an effective radiation dose of 14 mSv.

The amount of radiation in 18F-FDG is similar to the effective dose of spending one year in the American city of Denver, Colorado (12.4 mSv/year). For comparison, radiation dosage for other medical procedures range from 0.02 mSv for a chest x-ray and 6.5–8 mSv for a CT scan of the chest. Average civil aircrews are exposed to 3 mSv/year, and the whole body occupational dose limit for nuclear energy workers in the USA is 50mSv/year. For scale, see Orders of magnitude (radiation).

For PET-CT scanning, the radiation exposure may be substantial—around 23–26 mSv (for a 70 kg person—dose is likely to be higher for higher body weights).

Operation

Radionuclides and radiotracers

Main article: List of PET radiotracers

Schematic view of a detector block and ring of a PET scanner

 

Isotopes used in PET scans

Isotope	11C	13N	15O	18F	68Ga	64Cu	52Mn	55Co	89Zr	82Rb
Half-life	20 min	10 min	2 min	110 min	67.81 min	12.7 h	5.6 d	17.5 h	78.4 h	1.3 min

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. 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 continuing to be synthesized; as of this writing there are already dozens in clinical use and hundreds applied in research. In 2020 by far the most commonly used radiotracer in clinical PET scanning is the carbohydrate derivative fludeoxyglucose (18F) (18F-FDG). This radiotracer is used in essentially all scans for oncology and most scans in neurology, and thus makes up the large majority of radiotracer (>95%) used in PET and PET-CT scanning.

Due to the short half-lives of most positron-emitting radioisotopes, the radiotracers have traditionally been produced using a cyclotron in close proximity to the PET imaging facility. The half-life of fluorine-18 is long enough that radiotracers labeled with fluorine-18 can be manufactured commercially at offsite locations and shipped to imaging centers. Recently rubidium-82 generators have become commercially available. These contain strontium-82, which decays by electron capture to produce positron-emitting rubidium-82.

The use of positron-emitting isotopes of metals in PET scans has been reviewed, including elements not listed above, such as lanthanides.

Immuno-PET

The isotope ⁸⁹Zr has been applied to the tracking and quantification of molecular antibodies with positron emission tomography (PET) cameras (a method called "immuno-PET").

The biological half-life of antibodies is typically on the order of days, see daclizumab and erenumab by way of example. To visualize and quantify the distribution of such antibodies in the body, the PET isotope ⁸⁹Zr is well suited because its physical half-life matches the typical biological half-life of antibodies, see table above.

Emission

Schema of a PET acquisition process

To conduct the scan, a short-lived radioactive tracer isotope is injected into the living subject (usually into blood circulation). Each tracer atom has been chemically incorporated into a biologically active molecule. There is a waiting period while the active molecule becomes concentrated in tissues of interest; then the subject is placed in the imaging scanner. The molecule most commonly used for this purpose is F-18 labeled fluorodeoxyglucose (FDG), a sugar, for which the waiting period is typically an hour. During the scan, a record of tissue concentration is made as the tracer decays.

As the radioisotope undergoes positron emission decay (also known as positive beta decay), it emits a positron, an antiparticle of the electron with opposite charge. The emitted positron travels in tissue for a short distance (typically less than 1 mm, but dependent on the isotope), during which time it loses kinetic energy, until it decelerates to a point where it can interact with an electron. The encounter annihilates both electron and positron, producing a pair of annihilation (gamma) photons moving in approximately opposite directions. These are detected when they reach a scintillator 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 moving in approximately opposite directions (they would be exactly opposite in their center of mass frame, but the scanner has no way to know this, and so has a built-in slight direction-error tolerance). Photons that do not arrive in temporal "pairs" (i.e. within a timing-window of a few nanoseconds) are ignored.

Localization of the positron annihilation event

The most significant fraction of electron–positron annihilations results 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 the line of response, or LOR). In practice, the LOR has a non-zero width as the emitted photons are not exactly 180 degrees apart. If the resolving time of the detectors is less than 500 picoseconds rather than about 10 nanoseconds, it is possible to localize the event to a segment of a chord, 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 fewer events to achieve the same image quality. This technology is not yet common, but it is available on some new systems.

Image reconstruction

The raw data collected by a PET scanner are a list of 'coincidence events' representing near-simultaneous detection (typically, within a window of 6 to 12 nanoseconds of each other) 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 (i.e., the line of response (LOR)).

Analytical techniques, much like the reconstruction of computed tomography (CT) and single-photon emission computed tomography (SPECT) data, are commonly used, although the data set collected in PET is much poorer than CT, so reconstruction techniques are more difficult. Coincidence events can be grouped into projection images, called sinograms. The sinograms are sorted by the angle of each view and tilt (for 3D images). The sinogram images are analogous to the projections captured by computed tomography (CT) scanners, and can be reconstructed in a similar way. The statistics of data thereby obtained are 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. This contributes to PET images appearing "noisier" than CT. Two major sources of noise in PET are scatter (a detected pair of photons, at least one of which was deflected from its original path by interaction with matter in the field of view, leading to the pair being assigned to an incorrect LOR) and random events (photons originating from two different annihilation events but incorrectly recorded as a coincidence pair because their arrival at their respective detectors occurred within a coincidence timing window).

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. Disadvantages are that 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. Also, FBP treats the data deterministically—it does not account for the inherent randomness associated with PET data, thus requiring all the pre-reconstruction corrections described above.

Statistical, likelihood-based approaches: Statistical, likelihood-based iterative expectation-maximization algorithms such as the Shepp-Vardi algorithm are now the preferred method of reconstruction. These algorithms compute an estimate of the likely distribution of annihilation events that led to the measured data, based on statistical principles. The advantage is a better noise profile and resistance to the streak artifacts common with FBP, but the disadvantage is higher computer resource requirements. A further advantage of statistical image reconstruction techniques is that the physical effects that would need to be pre-corrected for when using an analytical reconstruction algorithm, such as scattered photons, random coincidences, attenuation and detector dead-time, can be incorporated into the likelihood model being used in the reconstruction, allowing for additional noise reduction. Iterative reconstruction has also been shown to result in improvements in the resolution of the reconstructed images, since more sophisticated models of the scanner physics can be incorporated into the likelihood model than those used by analytical reconstruction methods, allowing for improved quantification of the radioactivity distribution.

Research has shown that Bayesian methods that involve a Poisson likelihood function and an appropriate prior probability (e.g., a smoothing prior leading to total variation regularization or a Laplacian distribution leading to ${\displaystyle \ell _{1}}$-based regularization in a wavelet or other domain), such as via Ulf Grenander's Sieve estimator or via Bayes penalty methods or via I.J. Good's roughness method may yield superior performance to expectation-maximization-based methods which involve a Poisson likelihood function but do not involve such a prior.

Attenuation correction: Quantitative PET Imaging requires attenuation correction. In these systems attenuation correction is based on a transmission scan using ⁶⁸Ge rotating rod source.

Transmission scans directly measure attenuation values at 511keV. Attenuation occurs when photons emitted by the radiotracer inside the body are absorbed by intervening tissue between the detector and the emission of the photon. 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, in place of earlier equipment that 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. The advent of sub-nanosecond timing resolution detectors affords better random coincidence rejection, thus favoring 3D image reconstruction.

Time-of-flight (TOF) PET: For modern systems with a higher time resolution (roughly 3 nanoseconds) a technique called "Time-of-flight" is used to improve the overall performance. Time-of-flight PET makes use of very fast gamma-ray detectors and data processing system which can more precisely decide the difference in time between the detection of the two photons. Although it is technically impossible to localize the point of origin of the annihilation event exactly (currently within 10 cm) thus image reconstruction is still needed, TOF technique gives a remarkable improvement in image quality, especially signal-to-noise ratio.

Combination of PET with CT or MRI

Main articles: PET-CT and PET-MRI

Complete body PET-CT fusion image

 

Brain PET-MRI fusion image

PET scans are increasingly read alongside CT or magnetic resonance imaging (MRI) scans, with the combination (called "co-registration") giving both anatomic and metabolic information (i.e., 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 (so-called "PET-CT"). 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 anatomical variation, which is more common outside the brain.

At the Jülich Institute of Neurosciences and Biophysics, the world's largest PET-MRI device began operation in April 2009: a 9.4-tesla magnetic resonance tomograph (MRT) combined with a positron emission tomograph (PET). Presently, only the head and brain can be imaged at these high magnetic field strengths.

For brain imaging, registration of CT, MRI and PET scans may be accomplished without the need for an integrated PET-CT or PET-MRI scanner by using a device known as the N-localizer.

Limitations

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. Since the tracers are radioactive, the elderly and pregnant are unable to use it due to risks posed by 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 after radioisotope preparation. Organic radiotracer molecules that will contain a positron-emitting radioisotope cannot be synthesized first and then the radioisotope prepared within them, because bombardment with a cyclotron to prepare the radioisotope destroys any organic carrier for it. Instead, the isotope must be prepared first, then afterward, the chemistry to prepare any organic radiotracer (such as FDG) accomplished very quickly, in the short time before the isotope decays. Few hospitals and universities are capable of maintaining such systems, and most clinical PET is supported by third-party suppliers of radiotracers that can supply many sites simultaneously. This limitation restricts clinical PET primarily to the use of tracers labelled with fluorine-18, which has a half-life of 110 minutes and can be transported a reasonable distance before use, or to rubidium-82 (used as rubidium-82 chloride) with a half-life of 1.27 minutes, which is 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" (automated chemistry labs that are able to work with radioisotopes) 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. In recent years the shortage of PET scans has been alleviated in the US, as rollout of radiopharmacies to supply radioisotopes has grown 30%/year.

Because the half-life of fluorine-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.

History

The concept of emission and transmission tomography was introduced by David E. Kuhl, Luke Chapman 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. In 1975 tomographic imaging techniques were further developed by Michel Ter-Pogossian, Michael E. Phelps, Edward J. Hoffman and others at Washington University School of Medicine.

Work by Gordon Brownell, Charles Burnham and their associates at the Massachusetts General Hospital beginning in the 1950s 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 1961, James Robertson and his associates at Brookhaven National Laboratory built the first single-plane PET scan, nicknamed the "head-shrinker."

One of the factors most responsible for the acceptance of positron imaging was the development of radiopharmaceuticals. In particular, the development of labeled 2-fluorodeoxy-D-glucose (2FDG) by the Brookhaven group under the direction of Al Wolf and Joanna Fowler was a major factor in expanding the scope of PET imaging. 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.

The logical extension of positron instrumentation was a design using two 2-dimensional arrays. PC-I was the first instrument using this concept and was designed in 1968, completed in 1969 and reported in 1972. The first applications of PC-I in tomographic mode as distinguished from the computed tomographic mode were reported in 1970. It soon became clear to many of those involved in PET development that a circular or cylindrical array of detectors was the logical next step in PET instrumentation. Although many investigators took this approach, James Robertson and Zang-Hee Cho were the first to propose a ring system that has become the prototype of the current shape of PET.

The PET-CT scanner, attributed to David Townsend and Ronald Nutt, was named by Time as the medical invention of the year in 2000.

Cost

As of August 2008, Cancer Care Ontario reports that the current average incremental cost to perform a PET scan in the province is Can$1,000–1,200 per scan. This includes the cost of the radiopharmaceutical and a stipend for the physician reading the scan.

In the United States, a PET scan is estimated to be ~$5,000, and most insurance companies don't pay for routine PET scans after cancer treatment due to the fact that these scans are often unnecessary and present potentially more risks than benefits.

In England, the National Health Service reference cost (2015–2016) for an adult outpatient PET scan is £798.

In Australia, as of July 2018, the Medicare Benefits Schedule Fee for whole body FDG PET ranges from A$953 to A$999, depending on the indication for the scan.

Quality control

The overall performance of PET systems can be evaluated by quality control tools such as the Jaszczak phantom.

Brain metastasis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Brain_metastasis 

 

Micrograph showing a colorectal carcinoma metastasis to the cerebellum. HPS stain.

A brain metastasis is a cancer that has metastasized (spread) to the brain from another location in the body and is therefore considered a secondary brain tumor. The metastasis typically shares a cancer cell type with the original site of the cancer. Metastasis is the most common cause of brain cancer, as primary tumors that originate in the brain are less common. The most common sites of primary cancer which metastasize to the brain are lung, breast, colon, kidney, and skin cancer. Brain metastases can occur in patients months or even years after their original cancer is treated. Brain metastases have a poor prognosis for cure, but modern treatments are allowing patients to live months and sometimes years after the diagnosis.

Symptoms and signs

Brain metastasis in the right cerebral hemisphere from lung cancer shown on T1-weighted magnetic resonance imaging with intravenous contrast.

Because different parts of the brain are responsible for different functions, symptoms vary depending on the site of metastasis within the brain. However, brain metastases should be considered in any cancer patient who presents with neurological or behavioral changes.

Brain metastases can cause a wide variety of symptoms which can also be present in minor, more common conditions. Neurological symptoms are often caused by increased intracranial pressure, with severe cases resulting in coma. The most common neurological symptoms include:

• New onset headaches: headaches occur in roughly half of brain metastasis patients, especially in those with many tumors.
• Paresthesias: patients often present with (hemiparesis), or weakness on only one side of the body, which is often a result of damage to neighboring brain tissue.
• Ataxia: when metastasis occurs to the cerebellum, patients will experience various difficulties with spatial awareness and coordination.
• Seizures: when present, often indicates disease involvement of the cerebral cortex.

Causes

The most common sources of brain metastases in a case series of 2,700 patients undergoing treatment at the Memorial Sloan–Kettering Cancer Center were:

• Lung cancer, 48%
• Breast cancer, 15%
• Genitourinary tract cancers, 11%
• Osteosarcoma, 10%
• Melanoma, 9%
• Head and neck cancer, 6%
• Neuroblastoma, 5%
• Gastrointestinal cancers, especially colorectal and pancreatic carcinoma, 3%
• Lymphoma, 1%

Lung cancer and melanoma are most likely to present with multiple metastasis, whereas breast, colon, and renal cancers are more likely to present with a single metastasis.

Diagnosis

Resected fragments of a brain tumor, and in this case the very dark appearance supports a diagnosis of metastatic pigment-forming melanoma.

Brain imaging (neuroimaging such as CT or MRI) is needed to determine the presence of brain metastases. In particular, contrast-enhanced MRI is the best method of diagnosing brain metastases, though detection is primarily done by CT. Biopsy is often recommended to confirm diagnosis.

The diagnosis of brain metastases typically follows a diagnosis of a systemic cancer. Occasionally, brain metastases will be diagnosed concurrently with a primary tumor or before the primary tumor is found.

In brain metastasis due to malignant melanoma, MRI imaging showed high T1 and low T2 intensity due to the deposition of melanin in the brain. In susceptibility weighted imaging (SWI), it usually shows abnormal SWI hypointensity in larger proportion than brain metastasis caused by breast carcinoma.

Treatment

Treatment for brain metastases is primarily palliative, with the goals of therapy being reduction of symptoms and prolongation of life. However, in some patients, particularly younger, healthier patients, aggressive therapy consisting of open craniotomy with maximal excision, chemotherapy, and radiosurgical intervention (Gamma Knife therapy) may be attempted.

Symptomatic care

Symptomatic care should be given to all patients with brain metastases, as they often cause severe, debilitating symptoms. Treatment consists mainly of:

• Corticosteroids – Corticosteroid therapy is essential for all patients with brain metastases, as it prevents development of cerebral edema, as well as treating other neurological symptoms such as headaches, cognitive dysfunction, and emesis. Dexamethasone is the corticosteroid of choice. Although neurological symptoms may improve within 24 to 72 hours of starting corticosteroids, cerebral edema may not improve for up to a week. In addition, patients may experience adverse side effects from these drugs, such as myopathy and opportunistic infections, which can be alleviated by decreasing the dose.
• Anticonvulsants – Anticonvulsants should be used for patients with brain metastases who experience seizures, as there is a risk of status epilepticus and death. Newer generation anticonvulsants including Lamotrigine and Topiramate are recommended due to their relatively limited side effects. It is not recommended to prophylactically give anti-seizure medications when a seizure has not yet been experienced by a patient with brain metastasis.

Radiotherapy

Radiotherapy plays a critical role in the treatment of brain metastases, and includes whole-brain irradiation, fractionated radiotherapy, and radiosurgery. Whole-brain irradiation is used as a primary treatment method in patients with multiple lesions and is also used alongside surgical resection when patients have single and accessible tumors. However, it often causes severe side effects, including radiation necrosis, dementia, toxic leukoencephalopathy, partial to complete hair loss, nausea, headaches, and otitis media. In children this treatment may cause mental retardation, psychiatric disturbances, and other neuropsychiatric effects.

Surgery

Brain metastases are often managed surgically if they are accessible. Surgical resection followed by stereotactic radiosurgery or whole-brain irradiation deliver superior survival compared to whole brain irradiation alone. Therefore, in patients with only one metastatic brain lesion and controlled or limited systemic disease, a life expectancy of at least 3 months and a good performance status might be expected.

Chemotherapy

Chemotherapy is rarely used for the treatment of brain metastases, as chemotherapeutic agents penetrate the blood brain barrier poorly. However, some cancers such as lymphomas, small cell lung carcinomas (SCLC) and breast cancer may be highly chemosensitive and chemotherapy may be used to treat extracranial sites of metastatic disease in these cancers. The effectiveness and safety of using chemotherapy to treat a brain metastasis that came from a SCLC is not clear. An experimental treatment for brain metastases is intrathecal chemotherapy, a technique in which a chemotherapeutic drug is delivered via intralumbar injection into the cerebrospinal fluid. Current research on the treatment of brain metastases includes creating new drug molecules to effectively target the blood-brain barrier and studying the relationship between tumors and various genes. In 2015, the United States FDA approved Alecensa (alectinib) for use in patients with a specific type of non-small cell lung cancer (NSCLC; ALK-positive), a type of cancer which often metastasizes to the brain, whose condition worsened after use or were unable to take another medication, Xalkori (crizotinib).

Immunotherapy

Immunotherapy, for instance Anti-PD-1 alone or in combination with anti-CTLA-4, appears to be effective in some patients with brain metastases especially when these are asymptomatic, stable and not previously treated.

Prognosis

The prognosis for brain metastases is variable; it depends on the type of primary cancer, the age of the patient, the absence or presence of extracranial metastases, and the number of metastatic sites in the brain. For patients who do not undergo treatment the average survival is between one and two months. However, in some patients, such as those with no extracranial metastases, those who are younger than 65, and those with a single site of metastasis in the brain only, prognosis is much better, with median survival rates of up to 13.5 months. Because brain metastasis can originate from various different primary cancers, the Karnofsky performance score is used for a more specific prognosis.

Epidemiology

It is estimated that the worldwide incidence rate for brain metastases lies around 9% to 17%, based on the region of diagnosis. However, the baseline incidence rate of brain metastases were found to increase with improvements to brain imaging technology. Approximately 5 - 11% of brain metastasis were found to be deadly at 30 days, and 14 - 23% were found to be deadly at three months.

More cases of brain metastases were found in adults, compared to children. 67% to 80% of all cancer patients were found to develop brain metastases, as of 2012. Lung cancer, breast cancer and melanoma patients were found to be at the highest risk of developing brain metastases. However, recent trends in brain metastasis epidemiology have shown an increase in incidence for patients with renal, colorectal or ovarian cancers. Brain metastases are most commonly diagnosed within multiple intracranial areas within the context of extracranial diseases.

Both population studies and autopsy studies have historically been used to calculate the incidence of brain metastases. However, many researchers have stated that population studies may express inaccurate data for brain metastases, given that surgeons have, in the past, been hesitant to take in patients with the condition. As a result, population studies regarding brain metastases have historically been inaccurate and incomplete.

Recent advances in systemic treatments of brain metastases, such as radiosurgery, whole-brain radiotherapy and surgical resection has led to an increase in median survival rate of brain metastases patients.