Teachers Day at Rutherford Appleton Laboratory 2014

The Role of Physics in Nuclear Medicine

Dr Laura Harkness-Brennan

University of Liverpool

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http://ns.ph.liv.ac.uk/imaging-group/group-members/laura-harkness.php

Medical Imaging

Creating images of inside the body

Used in a non-invasive way to diagnose structural and biological problems

There are various established techniques used in hospitals

• Radiography

• MRI

• Ultrasound

• Nuclear imaging

• Physics, engineering, biology, chemistry, maths and computer science

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Nuclear Medical Imaging

Emission tomography is used to study biological functions. It complements anatomical imaging methods. It uses radioactive tracers, administered to the patient.

Single Photon Emission Computed Tomography (SPECT) uses gamma-ray emitting isotopes.

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The above left image shows a SPECT slice of the distribution of technetium exametazime within a patient’s brain. The above right image shows a Siemens brand SPECT scanner, consisting of two gamma cameras.

The technique requires delivery of a gamma-emitting radioisotope (a radionuclide) into the patient, normally through injection into the bloodstream. On occasion, the radioisotope is a simple soluble dissolved ion, such as a radioisotope of gallium (III). Most of the time, though, a marker radioisotope is attached to a specific ligand to create a radioligand, whose properties bind it to certain types of tissues. This marriage allows the combination of ligand and radiopharmaceutical to be carried and bound to a place of interest in the body, where the ligand concentration is seen by a gamma-camera.

To acquire SPECT images, the gamma camera is rotated around the patient. Projections are acquired at defined points during the rotation, typically every 3–6 degrees. In most cases, a full 360-degree rotation is used to obtain an optimal reconstruction. The time taken to obtain each projection is also variable, but 15–20 seconds is typical. This gives a total scan time of 15–20 minutes.

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The above image shows a SPECT machine performing a total body bone scan. The patient lies on a table that slides through the machine, while a pair of gamma cameras rotates around her.

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http://en.wikipedia.org/wiki/Single-photon_emission_computed_tomography

Positron Emission Tomography (PET) uses positron emitting isotopes (beta decay)

Positron emission tomography (PET) is a nuclear medicine, functional imaging technique that produces a three-dimensional image 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. Three-dimensional images of tracer concentration within the body are then constructed by computer analysis. In modern PET-CT scanners, three dimensional imaging is often accomplished with the aid of a CT X-ray scan performed on the patient during the same session, in the same machine.

The below left image of a typical positron emission tomography (PET) facility and the below right image shows a schema of a PET acquisition process.

Radioactive tracing is well researched to get the dose correct.

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If the biologically active molecule chosen for PET is fludeoxyglucose (FDG), an analogue of glucose, the concentrations of tracer imaged will indicate tissue metabolic activity by virtue of the regional glucose uptake. Use of this tracer to explore the possibility of cancer metastasis (i.e., spreading to other sites) is the most common type of PET scan in standard medical care (90% of current scans). However, on a minority basis, many other radioactive tracers are used in PET to image the tissue concentration of many other types of molecules of interest.

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

Gamma camera

Gamma cameras are based on 1950’s technology. A collimator is required to define the direction of gamma-rays. Gamma-rays are detected in a scintillator detector. Signals fed from an array of photomultiplier tubes into electronic logic circuits. An energy gate is set up. If the energy of the detected gamma‐rays is within the gate range then a count per gamma-ray is binned into 2D pixels

http://en.wikipedia.org/wiki/Gamma_camera

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The above right image shows examples of lung scintigraphy examination.

Collimators

Gamma-rays are uncharged so they can’t be deflected using electric or magnetic fields. You need to use a collimator to attenuate the gamma-rays via absorption or scatter.

A Parallel hole collimator provides direct projection of activity distribution onto a crystal without any magnification or reduction in size.

Other collimation schemes magnify or reduce the image to allow better visualisation of small organs or to allow large organs to be imaged with relatively small detector.

Magnification of the image and sensitivity changes as a function of distance from collimator.

Large hole diameters and short hole lengths gives the best sensitivity.

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Collimators’ geometry is chosen for differing clinical applications. They accept radiation only from a narrow cylinder defined by geometry

The cylinder defines the Line of Response (LoR). The line of response is the straight line of coincidence that allows the source of two 511 keV gamma photons, being emitted at almost 180 degrees to each other, to be identified.

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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.

Gamma-ray Detectors

Gamma‐ray detectors are a key component of all nuclear imaging systems, including the gamma camera.

Detectors must measure energy accurately and efficiently, with good timing resolution. Scintillator detectors are most common.

http://en.wikipedia.org/wiki/Gamma_spectroscopy

The equipment used in gamma spectroscopy includes an energy-sensitive radiation detector, electronics to process detector signals produced by the detector, such as a pulse sorter (i.e., multichannel analyser), and associated amplifiers and data readout devices to generate, display, and store the spectrum.

A scintillator uses a photomultiplier tube to multiply the current produced by incident radiation by as much as 100 million times (i.e., 160 dB), in multiple dynode stages, enabling (for example) individual photons to be detected when the incident flux is very low.

http://en.wikipedia.org/wiki/Photomultiplier

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Clinical Applications of SPECT

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SPECT is useful for assessing coronary artery disease and heart muscle damage following a heart attack.

Radiotracers often accumulate in cancerous cells found in the thorax, abdomen or brain.

Tomographic information aids in tumour detection and localisation against a complex background. It is also used in imaging of infection and inflammation and measurement of liver and kidney function.

http://en.wikipedia.org/wiki/Tomography

Tomography refers to imaging by sections or sectioning, through the use of any kind of penetrating wave. A device used in tomography is called a tomograph, while the image produced is a tomogram.

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Basic principle of tomography: superposition free tomographic cross sections S1 and S2 compared with the projected image P

How Positron Emission Tomography (PET) works

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Nuclear imaging is used to study biological functions: PET

Inject a radioactive biological compound into a patient such as 18F-FDG. The compound travels to the organ of interest (e.g. the tumour)

A positron is emitted which annihilates in the body. Two gamma rays emitted from the annihilation move away from each other at an angle of about 180 degrees. The gamma rays are detected outside of the body – Line of Response (LOR) and overlapping LOR’s show the location of the radiation.

PET Annihilation Events

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PET radionuclides decay by positron emission, (β+)

The positron is emitted with an initial kinetic energy, but then slows down in the medium.

When the slowed-down positron comes in close contact with a free or weakly bound electron, they annihilate each other.

The energy of each particle is released in the process as two back to back 511 keV photons to conserve momentum.

How a PET image is formed

Radiopharmaceuticals such as fluorodeoxyglucose (FDG) includes sugar (glucose) and the radioactive nuclide (18F, which is made in a cyclotron)

Uptake of glucose will be greater in areas of high metabolic rate (eg cancer cells)

PET detectors are arranged in an array to detect the back to back (±180°) emissions, and the line of response can be defined without collimators

The image is formed by looking at coincidence events at different angles

PET produces both planar and tomographic images

http://en.wikipedia.org/wiki/Scintillator

http://www.scionix.nl/crystals.htm

A scintillator is a material that exhibits scintillation — the property of luminescence when excited by ionising radiation.

The detectors are high atomic number (Z) scintillators such as BGO

http://en.wikipedia.org/wiki/Bismuth_germanate

or LSO

http://en.wikipedia.org/wiki/Lutetium_orthosilicate#Applications

These both have good stopping power so they are efficient although BGO has a poor energy resolution.

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Associated Problems

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Random: two annihilation events creating two photon pairs. One photon from each pair measured within time window (4 – 12ns)

Scattered: One annihilation event, but one or both photons scattered changing the line of response (50% of events from the scatter).

Clinical Applications of PET

It can be used to diagnose Alzheimer’s disease, Parkinson’s disease, epilepsy and other neurological conditions as it shows areas where brain activity differs from the norm.

PET measures metabolism and it can differentiate between malignant and non-malignant masses such as scar tissue formed from radiation therapy

PET can perform accurate attenuation correction making it possible to relate measured count rates to absolute tracer concentrations.

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SPECT vs PET

SPECT

Radiotracers are less expensive and more abundant

The radionuclides generally have longer half-lives so they can travel further than PET radionuclides, so you don’t need cyclotron in the hospital

As the radionuclide emits a single photon you can look at two different tracers at the same time to study multiple biological functions

However, SPECT is not suitable for accurate quantitative measurement

PET

PET has an accurate photon attenuation correction

It has a superior, depth independent spatial resolution (20mm for SPECT but 10mm for PET)

It has improved image contrast and higher count rate than PET as it can remove the need for collimators because the source is collinear.

Radiotracers

An ideal source for a radiotracer includes:

No secondary emissions (this minimises the dose);

A half-life just big enough in respect to scan time (this minimises the dose);

Non-toxic;

Gamma energy of about 100 to 550 keV is sufficiently penetrating to escape the body but low enough in energy to be stopped by the detector;

The possibility of producing them locally, or semi-locally;

Iodine is selectively taken up by the thyroid and used to measure thyroid size and efficiency

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Technetium-99m is a metastable nuclear isomer of technetium-99, symbolised as 99mTc that is used in tens of millions of medical diagnostic procedures annually, making it the most commonly used medical radioisotope.

99mTc is the most commonly used isotope in nuclear medicine

http://en.wikipedia.org/wiki/Technetium-99m

It is ideal with a bout a six hour half-life

There is no beta emission

The parent isotope is 99Molybdenum which is produced from a nuclear reactor with a half-life of about 66 hours.

http://en.wikipedia.org/wiki/Isotopes_of_molybdenum

99mTc can be ‘locally produced’ from a radionuclide generator

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The half-life is the time taken for the activity (A) of a radioactive material to halve. It is an exponential function

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Where At is the activity at time t, A0 is the original activity and l is the decay constant

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PET radiotracers

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Next Generation Imaging

Medical imaging is a constantly advancing field however lots of the technology is older than 40 years

Research is taking place into new techniques, detectors, image processing methods, high performance computing and the development of new radiotracers

The University of Liverpool is working on:

SmartPET for small animals

ProSPECTus – the next generation SPECT

Imaging during radiotherapy for dosimetry

http://ns.ph.liv.ac.uk/imaging-group/projects/smartpet/index.php

SmartPET

Commercial PET systems use scintillator materials. These have excellent time resolution, good spatial resolution and poor energy resolution.

The University of Liverpool project uses semiconductor material such as Germanium.

The prototype Small Animal ReconsTructive PET (SmartPET) has two double sided HPGe strip detectors electronically segmented to provide 144 5x5x20 pixels and the spatial resolution of the system is less than 1mm^3

Due to energy resolution (2keV at 511keV) scatter data can be used or rejected unlike current systems this can lead to cleaner images.

Successful imaging of point and line sources

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Medical ProSPECTus Next Generation SPECT

£1.1 million project

Prototype system

High-sensitivity alternative to SPECT

Different method of imaging the gamma radiation

Uses semiconductor detectors

http://ns.ph.liv.ac.uk/imaging-group/projects/medical_compton/index.php

Conventional SPECT uses 1 gamma ray in every 3000 and is incompatible with MRI

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http://en.wikipedia.org/wiki/Magnetic_resonance_imaging

ProSPECTus uses one gamma ray in every 30 and is compatible with MRI

Multi-isotope imaging can take place with a lower dose to the patient or shorter data acquisition times.

Compton Imaging

Gamma rays interact in two detectors. The path of each gamma ray is reconstructed as a cone. The source of radiation located at the maximum overlap of the cones.

The gamma-ray source is located as a “hot-spot” on the image.

Medical Imaging – ProSPECTus as the next generation SPECT

Criteria:

A prototype system for use with current medical radionuclides;

It has a high sensitivity with excellent image qualities;

It has MRI compatibility.

Final Design:

It is optimised for imaging gamma rays from 99mTc;

It has a Si(Li) scatter detector and a HPGe absorber detector;

It has a custom–built cryostat and digital electronics.

A cryostat (from cryo meaning cold and stat meaning stable) is a device used to maintain low cryogenic temperatures of samples or devices mounted within the cryostat. It is required because parts of the apparatus need to be very cold to work properly.

http://en.wikipedia.org/wiki/Cryostat

Preclinical trials are in progress. The ProSPECTus images are being compared with images from current clinical scanners.

Next Generation SPECT Imaging – Boron Neutron Capture Therapy

Neutron capture therapy (NCT) is a non-invasive therapeutic modality for treating locally invasive malignant tumours such as primary brain tumours and recurrent head and neck cancer. It is a two-step procedure: first, the patient is injected with a tumour localizing drug containing a non-radioactive isotope that has a high propensity or cross section (σ) to capture slow neutrons. The cross section of the capture agent is many times greater than that of the other elements present in tissues such as hydrogen, oxygen and nitrogen. In the second step, the patient is radiated with epithermal neutrons, which after losing energy as they penetrate tissue, are absorbed by the capture agent which subsequently emits high-energy charged particles, thereby resulting in a biologically destructive nuclear reaction (See image below).

Boron neutron capture therapy (BNCT) can be performed at a facility with a nuclear reactor or at hospitals that have developed alternative neutron sources. A beam of epithermal neutrons penetrates the brain tissue, reaching the malignancy. Once there the epithermal neutrons slow down and these low-energy neutrons combine with boron-10 (delivered beforehand to the cancer cells by drugs or antibodies) to form boron-11, releasing lethal radiation (alpha particles and lithium ions) that can kill the tumour.

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All of the clinical experience to date with NCT is with the non-radioactive isotope boron-10, and this is known as boron neutron capture therapy (BNCT). At this time, the use of other non-radioactive isotopes, such as gadolinium, has been limited, and to date, it has not been used clinically. BNCT has been evaluated clinically as an alternative to conventional radiation therapy for the treatment of malignant brain tumours (gliomas), and more recently, recurrent, locally advanced head and neck cancer.

http://en.wikipedia.org/wiki/Boron_neutron_capture_therapy

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This is a new project to develop real-time imaging for boron neutron capture therapy.

Boron is administered to the patient (like a radiotracer), and the radiotherapy is “activated” by targeting the boron with neutrons.

A lot of local damage is done by the alpha particle that is emitted but as it is short range there is minimum damage to healthy tissue.

The project involves a dual PhD studentship with National Tsing Hua University to investigate imaging the emission point of the gamma-rays during the therapy (real-time dosimetry)

The Challenges (hopefully our A level physics students will take up some of these challenges)

Improving diagnostic image quality

Improving quantification in imaging

Reducing dose to patients

Overcoming the 99mTc shortage

Producing dynamic imaging/organ gating

Enabling imaging during proton therapy

Enabling three dimensional real-time imaging during surgery

‘Big data’

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