Periodic Reporting for period 5 - 4D-PET (Innovative PET scanner for dynamic imaging)
Okres sprawozdawczy: 2023-08-01 do 2023-12-31
The human brain is the most complex object of the Universe. It contains about 100 billion neurons, almost the same number as stars in our Galaxy, and more than 100 trillion synapsis between neurons. But what makes it really unique is its inner workings and functions. Neuroscientists are very far from fully understanding the interplay between brain structure, neuro-transmitters and oxygen consumption. They need new and more precise tools to image the brain in a non-invasive way, while performing regular activities.
Positron Emission Tomography (PET) is an imaging technique that uses specific molecules that are injected intravenously and are consumed by the human body to perform its tasks. Tracking the position of those molecules in the head enables to study the function of the brain. This is possible because the atomic composition of those molecules is slightly modified to include a positron emitter atom, usually 18F. Fluorine is of interest because the negative fluorine ion (-F) behaves chemically similar to the hydroxyl ion (OH-), which is commonly found in organic molecules. The positron emitted annihilates immediately when it encounters an electron in its surroundings. Then, two photons are produced in opposite directions, both having the same energy corresponding to the mass of the electron or positron (511 kilo electron volts). These photons are gamma-rays that easily pass through the body without interacting and are detected using external gamma-ray cameras.
New drugs have been recently approved (Lecanemab, Donanemab) that, for the first time in history, appear to slow significantly cognition decline in Alzheimer´s patients. This might trigger a tsunami of demand in brain examinations with PET. There is not enough number of PET scanners in the World to satisfy such expected demand. Moreover, doctors will need to perform a follow-up of the therapy in order to check whether the treatment is being effective. This implies examining the same patient several times within a year. This is not possible with current scanners, due to its low sensitivity, without surpassing the total allowed dose per year.
The main objective of 4D-PET is to develop an innovative brain PET scanner based in a new detector concept that stores 3D position and time of every single gamma ray interaction with unprecedented resolution and sensitivity.
Positron Emission Tomography (PET) is an imaging technique that uses specific molecules that are injected intravenously and are consumed by the human body to perform its tasks. Tracking the position of those molecules in the head enables to study the function of the brain. This is possible because the atomic composition of those molecules is slightly modified to include a positron emitter atom, usually 18F. Fluorine is of interest because the negative fluorine ion (-F) behaves chemically similar to the hydroxyl ion (OH-), which is commonly found in organic molecules. The positron emitted annihilates immediately when it encounters an electron in its surroundings. Then, two photons are produced in opposite directions, both having the same energy corresponding to the mass of the electron or positron (511 kilo electron volts). These photons are gamma-rays that easily pass through the body without interacting and are detected using external gamma-ray cameras.
New drugs have been recently approved (Lecanemab, Donanemab) that, for the first time in history, appear to slow significantly cognition decline in Alzheimer´s patients. This might trigger a tsunami of demand in brain examinations with PET. There is not enough number of PET scanners in the World to satisfy such expected demand. Moreover, doctors will need to perform a follow-up of the therapy in order to check whether the treatment is being effective. This implies examining the same patient several times within a year. This is not possible with current scanners, due to its low sensitivity, without surpassing the total allowed dose per year.
The main objective of 4D-PET is to develop an innovative brain PET scanner based in a new detector concept that stores 3D position and time of every single gamma ray interaction with unprecedented resolution and sensitivity.
INNOVATIVE 4D-PET GAMMA RAY DETECTOR TECHNOLOGIES
All gamma-ray detectors in commercial PET scanners use a matrix of high density scintillating crystal thin pixels, of about 4x4mm2 entrance surface and 20mm thickness, to stop the gamma-rays. The energy of the gamma-rays is converted inside the crystal pixels into light photons, which are carried through the pixels to a matrix of photo-sensors (SiPMs, Silicon Photo Multipliers). This produces only 2D information of the impact of the gamma ray inside the crystal but not along the pixel direction (Depth Of Interaction, DOI). Since the pixels are long (about 20mm) this lack of information produces a blurring in the image if the detectors are near the body to be scanned. The main 4D-PET challenge is to design a new detector technology able to provide not only the 3D (X, Y and DOI) impact position of each gamma ray inside the detector block, but also the time of the impact with excellent resolution.
Several innovative gamma-ray detector technologies have been studied thoroughly during the first 3 years of the project. Horizontal scintillating crystal Slabs with lateral photo-sensor readout was the original and innovative solution studied at the beginning of the project. However, Vertical scintillating crystal Slabs was the final adopted design, due to simplicity and lower costs. In this configuration, the slab hit defines one dimension, in an analog way to the pixels. The other 2 spatial dimensions are determined through the light distribution in the SIPM matrix. We have obtained spatial resolutions in the order of a millimeter in the 2D SiPM matrix and 5mm in the DOI. Resolution in the arrival time of the gamma-rays is around 250 picoseconds.
We also studied Metacrystal technology. In this configuration, a sandwich is made by alternating thin layers (about 200 microns) of high density scintillating crystals and thin layers of low density but very fast scintillating crystals. The high-density material stops the gamma-rays and the fast crystal provides the timing information. This is a very promising technology but it was not selected since it is not mature.
SCANER PROTOTYPES BUILT
The new 4D-PET detector technology has been used to develop of a scanner prototype dedicated to the human brain examination. The scanner ergonomics has been designed together with the Department of Nuclear Medicine at CHUV (Centre Hospitalier Universitaire Vaudois) in Lausanne.
A preclinical prototype to examine the head of mice has also been built with the same technology. The brain of a mouse has a size of only few millimetres and therefore to be able to visualize the detailed structure of its head and quantify, for instance, the amyloid deposit content, is very challenging.
A member of the 4D-PET team obtained a grant in 2020 from the Spanish Ministry of Health, through the Regional Government of Valencia, to build a Total-Body PET. Most commercial PET scanners are Whole-Body, and consist of a ring of gamma ray detectors. Only the part of the body that is inside the ring is imaged (typically 20cm) and hence the bed carries the whole body through the ring. A Total-Body PET is a scanner much longer in the direction of the bed than Whole-Body PET scanners. The same gamma-ray detector technology developed in 4D-PET ERG-AdG has also been used to construct a Total-Body PET of 65cm length. This is the first and only Total-Body PET scanner in Spain. There are only two companies in the World that produce Total-Body PET scanners: SIEMENS Healthineers and United Imaging, from China.
DISEMINATION AND EXPLOITATION
More than 50 papers have been published during this ERC-AdG, including two PhD theses. Dissemination has been performed through 22 oral presentations in international scientific conferences and workshops. 8 patents have been filed to protect the intellectual property. A large effort has been made to exploit the results, including contacts with several European and American companies. The ERC-AdG had a large positive impact in the development of the I3M institute and on the young researchers that have participated in the project, with many of them consolidating their carriers in Science or in Industry.
All gamma-ray detectors in commercial PET scanners use a matrix of high density scintillating crystal thin pixels, of about 4x4mm2 entrance surface and 20mm thickness, to stop the gamma-rays. The energy of the gamma-rays is converted inside the crystal pixels into light photons, which are carried through the pixels to a matrix of photo-sensors (SiPMs, Silicon Photo Multipliers). This produces only 2D information of the impact of the gamma ray inside the crystal but not along the pixel direction (Depth Of Interaction, DOI). Since the pixels are long (about 20mm) this lack of information produces a blurring in the image if the detectors are near the body to be scanned. The main 4D-PET challenge is to design a new detector technology able to provide not only the 3D (X, Y and DOI) impact position of each gamma ray inside the detector block, but also the time of the impact with excellent resolution.
Several innovative gamma-ray detector technologies have been studied thoroughly during the first 3 years of the project. Horizontal scintillating crystal Slabs with lateral photo-sensor readout was the original and innovative solution studied at the beginning of the project. However, Vertical scintillating crystal Slabs was the final adopted design, due to simplicity and lower costs. In this configuration, the slab hit defines one dimension, in an analog way to the pixels. The other 2 spatial dimensions are determined through the light distribution in the SIPM matrix. We have obtained spatial resolutions in the order of a millimeter in the 2D SiPM matrix and 5mm in the DOI. Resolution in the arrival time of the gamma-rays is around 250 picoseconds.
We also studied Metacrystal technology. In this configuration, a sandwich is made by alternating thin layers (about 200 microns) of high density scintillating crystals and thin layers of low density but very fast scintillating crystals. The high-density material stops the gamma-rays and the fast crystal provides the timing information. This is a very promising technology but it was not selected since it is not mature.
SCANER PROTOTYPES BUILT
The new 4D-PET detector technology has been used to develop of a scanner prototype dedicated to the human brain examination. The scanner ergonomics has been designed together with the Department of Nuclear Medicine at CHUV (Centre Hospitalier Universitaire Vaudois) in Lausanne.
A preclinical prototype to examine the head of mice has also been built with the same technology. The brain of a mouse has a size of only few millimetres and therefore to be able to visualize the detailed structure of its head and quantify, for instance, the amyloid deposit content, is very challenging.
A member of the 4D-PET team obtained a grant in 2020 from the Spanish Ministry of Health, through the Regional Government of Valencia, to build a Total-Body PET. Most commercial PET scanners are Whole-Body, and consist of a ring of gamma ray detectors. Only the part of the body that is inside the ring is imaged (typically 20cm) and hence the bed carries the whole body through the ring. A Total-Body PET is a scanner much longer in the direction of the bed than Whole-Body PET scanners. The same gamma-ray detector technology developed in 4D-PET ERG-AdG has also been used to construct a Total-Body PET of 65cm length. This is the first and only Total-Body PET scanner in Spain. There are only two companies in the World that produce Total-Body PET scanners: SIEMENS Healthineers and United Imaging, from China.
DISEMINATION AND EXPLOITATION
More than 50 papers have been published during this ERC-AdG, including two PhD theses. Dissemination has been performed through 22 oral presentations in international scientific conferences and workshops. 8 patents have been filed to protect the intellectual property. A large effort has been made to exploit the results, including contacts with several European and American companies. The ERC-AdG had a large positive impact in the development of the I3M institute and on the young researchers that have participated in the project, with many of them consolidating their carriers in Science or in Industry.
The measured sensitivity of the 4D-PET Brain scanner is 14,7%, and the spatial resolution is 1,25 mm at the centre of the FOV, both significantly better than commercial scanners. The new PET design has radically improved state-of-the-art PET performance features, overcoming limitations of current PET technology and opening up new diagnostic and brain research venues. These performance features are needed for the visualization of several critical small structures in the brain (substantia nigra and raphe nucleus) involved in mental disorders. 3 patients have been examined at Hospital “La Fe”, Valencia, Spain, with the new 4D-PET brain scanner.
The spatial and temporal resolution of the preclinical PET scanner for examining the head of a mouse are 0.8mm and 200picoseconds (ps), respectively. Furthermore, an inner gamma-ray detector layer closer to the brain has been built with a timing resolution of 130ps.
The spatial and temporal resolution of the preclinical PET scanner for examining the head of a mouse are 0.8mm and 200picoseconds (ps), respectively. Furthermore, an inner gamma-ray detector layer closer to the brain has been built with a timing resolution of 130ps.