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Periodic Report Summary 3 - TRIMAGE (A dedicated trimodality (PET/MR/EEG) imaging tool for schizophrenia)

Project Context and Objectives:
Schizophrenia is a severe mental disorder, characterized by profound disruptions in thinking, affecting language, perception, and the sense of self. It often includes psychotic experiences, such as hearing voices or delusions. Schizophrenia disorders manifest themselves early in life during very active life periods of education and productive work and can impair functioning through the loss of an acquired capability to earn a livelihood, or the disruption of studies. This causes a high social and economic burden on European societies. In most of the cases, if correctly diagnosed, schizophrenia can be treated, and people who are affected can lead a productive life and be integrated in society. Schizophrenia is usually studied using a translational approach: psychological, social and biological parameters are acquired and analyzed together, but the early diagnosis still remains a critical challenge. Currently, there is a strong need for an imaging tool that facilitates the diagnosis of schizophrenia early during development. It is important to stress that precise and early diagnosis cannot be achieved with a single measurement. Additionally, an off-line combination of data acquired separately could be insufficient, because several correlated patient-specific signals may vary over time. As a consequence, the full integration of different diagnostic modalities into a seamless clinical tool is necessary for the application of multiparametric measurements in all schizophrenia patients and especially for prodromic patients. Such a tool is not available today.
The main objectives of this project are two-fold: (a) to build and optimise an integrated diagnostic solution including a molecular imaging tool based on simultaneous Positron Emission Tomography (PET), Magnetic Resonance (MR) and Electroencephalography (EEG), and (b) to validate the new tool with specific biomarkers for detecting characteristic patterns in asymptomatic and at-risk patients and for monitoring disease follow-up during drug therapy.

The goals of this project will be achieved by the scientific and technological developments in both the medical and technological fields. These developments will be carried out following three strongly correlated S&T sub-objectives:

Sub-objective 1 (clinical) - Find new biomarkers and define a suitable multimodal paradigm with already available PET, MR, EEG and PET/MR systems that could provide clinical evidence on the feasibility of advanced schizophrenia diagnosis. Specific biomarkers that synergistically define the disease signature are still unavailable and need to be developed.

Sub-objective 2 (technological) - Construct and test an optimized cost-effective trimodality imaging instrument (brain PET/MR/EEG) for diagnosis, monitoring and follow-up of schizophrenia disorders. This leads to the optimization of well established imaging modalities and their full integration in a novel dedicated trimodal instrument. In combination with the new set of biomarkers, the brain PET/MR/EEG scanner will represent a complete turn-key solution for the early diagnosis of schizophrenia.

Sub-objective 3 (clinical) - Validate the trimodal imaging device with regard to the results and the clinical data obtained during the development of the sub-objective 1.

The final aim of the project is to create a trimodal, cost-effective imaging tool consisting of PET/MR/EEG using cutting edge technology with performance beyond the state of the art. The tool is intended for broad distribution so as to enable effective early diagnosis of schizophrenia and possibly other mental disorders.
Project Results:
The recruitment of patients and healthy volunteers required for defining a suitable paradigm to be validated on the trimodal imaging PET/MR/EEG device started in 2015 at TUM (20 patients and 20 healthy volunteers) and in late 2016 at Jülich (20 patients and 20 healthy volunteers) following the approval by the respective Ethics Committee and Radiation Protection Committee for both institutions. The experimental procedure at TUM was based on the 3T mMR tomograph and the tracer used was [18F]-Dopa; 39 subjects have been scanned so far (24 patients and 15 controls). The experimental procedure at Jülich was performed on the available PET/MR/EEG scanner. The mismatch negativity (MMN) paradigm has been identified as a good marker and the used tracer was [11C]-ABP688. MRS/MRI scans were performed on the Siemens MR-Brain PET unit. The results of the pilot study both in Munich and Julich have been published in the journal European Psychiatry (A. Del Guerra et al., 2018, vol. 50, 7-20) and are very promising.

As for the PET/MR/EEG scanner, the PET system design was completed in 2015. The PET ring is a full ring composed by 18 rectangular sectors on a cylindrical geometry, with an inner radius of 157.2 mm and an axial length of 165 mm. Each sector is made of 3 square detectors, axially juxtaposed of size 52.8 mm, each one hosted in an RF shielded cassette. A Monte Carlo model of the TRIMAGE scanner using the Monte Carlo toolkit GATE was developed for the simulation. The PET image reconstruction was developed to accommodate the TRIMAGE scanner geometry. The simulation gives a sensitivity of the scanner of about 7% at the centre of the FOV and a spatial resolution of about 2 mm (FWHM), i.e., well beyond the PET performance of the available 3T PET/MR whole body systems. The SiPM photodetectors, the TRIROC ASIC, the DAQ electronics and the mechanics of the PET scanner has been fully designed, constructed and assembled. MR compatibility assessment has been done on individual PET components and on the relevant parts of the system. The results obtained with a point-like radioactive source on two completely assembled detectors in coincidence give an energy resolution of about 20% (FWHM) and a coincidence time resolution of about 600 ps (FHWM). The entire PET tomograph is now being assembled to be fully tested in Pisa.

As for the MR scanner, the full specifications of the 1.5 T magnet were decided, and the order was placed with the manufacturer (SSI, USA) in 2015. End of March 2017 the magnet was shipped to RS2D, and the installation started. The gradient coils were also delivered, and they work to specs both as strength and uniformity region (250 mm DSV on X, Y, Z axis) The inner diameter of the gradient coil is 580 mm and the DSV is 300mm. The necessary specific electronic /hardware components of the MRI system were developed (e.g., amplifier, gradient amplifier controller, coil interface box). The RF coil was manufactured by Affinity imaging and was delivered in March 2018 to RS2D. The coil is now working and can be used as a transmit/receive birdcage coil or as transmit birdcage and 8 receive array since May 2018. The development of the necessary MRI sequences (including MPRAGE, and EPI) has been implemented on a preclinical PET/MR system and transferred to the TRIMAGE MR scanner. MR attenuation correction for PET was developed based on external attenuation maps given from specific subjects. The 1.5T-720 mm cryogen-free magnet now works to specifications.

All the steps have been completed to identify the site for the final installation of the TRIMAGE scanner that was shifted from Julich to Pisa. There will be a fully new site inside the University Hospital, that is now in preparation. We are now working for the Radiation Protection, Ethics and Medical device application. The three relative documents are in preparation.

A project logo, a brochure set and documentation templates were delivered. The TRIMAGE website is online and is being maintained with the latest updates coming from the consortium. The number of TRIMAGE publications increased substantially, as project results became available. As of today, the publication list accounts for 16 scientific journal articles, 10 conference presentations and 2 other presentations.

A series of workshop on PET/MR has been co-organized yearly from 2014 to 2018. Papers from these workshops have been or will be published on special issues of International Journals. Three training schools on PET/MR have been organized: the first one in Jülich in March 2016, the second in Lisbon in May 2017, a third one in Isola d’Elba in 2018. A dedicated workshop on "Schizophrenia and other mental disorders" was organized in June 2017 in Pisa.
Potential Impact:
Schizophrenia is a chronic disorder that affects about 7 per 1000 of the adult population. Several expert reports clearly demonstrate the economic impact of schizophrenia and the market potential for a device as proposed by TRIMAGE. Schizophrenia is the second most costly disease in terms of the average cost per patient with an average cost being higher than that for cancer and stroke. The earlier the treatment is initiated, the more effective it is. However, a significant number of people with schizophrenia do not receive any medication or are not yet receiving timely, adequate treatment. The WHO estimates that more than 50% of persons with schizophrenia do not receive appropriate care.

Diagnoses of mental disorders are often based on the clinical expertise of the treating physician. This is true also for the treatment: whether the patient responds to a given treatment can currently be assessed only by monitoring the clinical course (2-6 weeks), a long time for the patient and his/her family and for the health system. The trimodality imaging (PET/MR/EEG) device that we are developing in this project aims to give the clinicians an effective tool for the diagnosis and choice of treatment for mental health disorders such as schizophrenia. Early diagnosis of schizophrenia could provide the opportunity to intervene earlier and, thus, to avert the trajectory to psychosis.

The final product of the TRIMAGE project, i.e., the PET/MR/EGG brain scanner will have a strong technological impact, not limited to the field of schizophrenia and brain disorders. More innovations will result from side tasks of the project. Some of the expected outcomes, which will have a technological impact, are:

i)-Progress in SiPM fabrication and readout,

ii)-New methods for improved DoI information and sensitivity optimization in PET,

iii)-Improved algorithms for PET/MR attenuation correction and image quantification,

iv)-Design, integration and performance evaluation of a PET/MR compatible insert,

v)-Realistic GATE simulations using computational brain phantoms,

vi)-Identification of Schizophrenia biomarkers, through a multimodal approach,

vii)-Realization of a targeted clinical study using the recently introduced PET/MR scanners.

The TRIMAGE project is based in an emerging area of multimodal brain imaging applications, where new kinds of expertise are being introduced. In order to reinforce the future generation of scientists for continuing development in these specialised emerging fields, TRIMAGE partners participate in the following actions:

i)-Training of young scientists via lectures at universities, and education of young researchers during practical training sessions as well as seminars.

ii)-Practical skills have been developed by supervising diplomas and doctoral theses.Where appropriate, exchanges have been organised for PhD/Post doc students between TRIMAGE partners.

iii) Organization of scientific schools and workshops.

In parallel to more general external communication, TRIMAGE aims to include education within medical programs to help open up a new generation of clinicians to this technology at national and European levels, in particular with psychiatrists, clinicians and doctors. Partners will look to participate in topical workshops and seminars aimed at stressing the interdisciplinary character of biomedicine with particular reference to the emerging area of multimodal imaging and personalised therapeutic treatments via biomarkers identification.
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