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MINDVIEW Report Summary

Project ID: 603002
Funded under: FP7-HEALTH
Country: Spain

Periodic Report Summary 2 - MINDVIEW (Multimodal Imaging of Neurological Disorders)

Project Context and Objectives:
The key concept behind this proposal is the development of a very high resolution and high efficiency brain dedicated Positron Emission Tomograph (PET) imager that can visualize neurotransmitter pathways and their disruptions in the quest to better diagnose and consequently to better treat schizophrenia. In addition, the plan is for this compact PET imager to be integrated with a Magnetic Resonance Imager Radio Frequency (MRI RF) system to be able to operate as a brain insert in a hybrid imaging setup with practically any MRI scanner.
From the technical point of view, we propose to optimize the PET technology for imaging of the human brain with the accuracy typically achieved for small animal brain imaging. To achieve this, we will incorporate the solid state based MRI-compatible PET modules that will be designed to achieve below systemic 1mm spatial resolution in a tomographic reconstruction of the human brain.
We aim to achieve the level of PET-MRI compatibility allowing for simultaneous PET and MRI imaging. By combining PET measurements of neurotransmission with fMRI (functional MRI) measurements of Blood Oxygen Level Detection (BOLD) signal changes we will advance to a position where it is possible to learn more about the neurochemical determination of neural activity reflected in BOLD signal changes.
The novelty is that both the PET and RF coil systems are integrated into a portable and compact design dedicated to brain examination. This will allow current MR equipment to be easily upgraded into PET/MR systems.
To achieve its diagnostic goal, MINDView will be paired with the set of dedicated specific PET imaging agents and endogenous compounds that will be labeled with short-lived positron isotopes. The goal is that dopaminergic, glutamatergic and other pathways will be able to be studied with the new high performance imaging tool. Innovative paradigms such as activation and perturbation and their impact on brain function will be in focus.

Project Results:
During this reporting period the most significant achievement in the detector area is the confirmation of a high detector block performance using a single monolithic 20 mm thick, 50x50 mm LYSO crystal. The consortium decided to add a retroreflector layer at the entrance scintillator surface improving all parameters namely an average detector spatial resolution of 1.2 mm (corroborated with modelled data and for all DOI layers), DOI FWHM of about 4 mm, and energy resolutions of about 13% also for the whole crystal volume.

On the Electronics WP there have been one major result to be highlighted, the ADC with 66 channels 12 bit each, has been successfully been tested in different setups. The trigger board supporting the 60 detectors of the 3 rings is currently being under tests.

A slight delay of the final RF coil design has been faced. As of now the optimization is not finished. The next step it to implement the proposed improvements and measure the coil again. It is planned to have a first coil finished by the 21st of November 2016 to be installed at the partner site in Munich. After that a second coil will be build up for a GE system for the Karolinska Site in Sweden as it seems it is not possible for the site to use a Siemens system as in Munich.

The first prototype ring has been built and successfully tested outside and inside a 3T MR. The system reaches the expected spatial resolution of almost 1.5 mm using Derenzo-like phantoms. Average energy resolution for the whole set of detectors is of about 14.5% allowing for an accurate scatter correction. The system used carbon fiber screen for the RF field that have worked well in the MR environment. An electronic cabinet containing the ADCs and Trigger boards has also been tested inside a 3T MR room.

Within the MindView project, a collaboration between Bencar (BC) and Karolinska Institute (KI) has been carried out around the chemistry development of the molecular probes. Bencar focus on developing a new technology for the new 11C-methyl iodide system in a mini cleanroom concept. Producing 11C-methyl iodide from 11C-carbon dioxide needs that the 11C-methane can be produced using proven methods then has to be integrated in our system. We need to be able to control the temperature in the range of 400oC and also have access to iodine in the plasma we intend to generate. Currently is undergoing the building system including the generation of a cold plasma at the Bencar lab. Later they will test the system including the use radioactivity at the Karolinska PET center with various types of plasma reactors.

Clinical partners have focus onto neurodegenerative disorders such as Alzheimer’s disease (AD). Age-associated neurodegenerative disorders are accompanied by brain atrophy and vascular lesions, which substantially complicates accurate PET measurements and thus challenge the MindView system under the construction. Dr. Igor Yakushev, a co-investigator of the MINDVIEW project, spent several months at the Karolinska Institute at Stockholm to generate cooperative projects between the two clinical sites involved in the MINDVIEW project. As primary study at the TUM, we have established a tau PET tracer automation, CMC and imaged tau proteins, a pathological feature of AD, in transgenic mice and patients with mild cognitive impairment (MCI) and dementia due to AD.

Potential Impact:
MindView will be a real breakthrough in terms of new tools for imaging that will allow the definition of parameters allowing patient stratification in schizophrenia and depression diseases. This should also lead in the future to development of the next generation of drugs for treating those disorders. Furthermore, the new tools developed will allow for an extension of techniques that are currently only available to very few hospitals.

The significance of this project is substantial. Neuropsychiatric disorders affect a large part of the population, and cause a great deal of suffering both to the patients and to those close to them. The cost to society is substantial. A three-year study covering 30 European countries - the 27 European Union member states plus Switzerland, Iceland and Norway - and a population of 514 million people, looking at about 100 illnesses covering all major brain disorders (including depression and schizophrenia, concluded that Europeans are plagued by mental and neurological illnesses, with almost 165 million people or 38 percent of the population suffering each year from a brain disorder.

Mental disorders are on the rise in the EU. Depression is already the most prevalent health problem in many EU-Member States. More specifically, the prevalence of schizophrenia and depression in year 2005 were 0,8% (3,7 million) and 6,9% (18,4 million), whereas in year 2011 were 1,2% (5 million) and 6,9% (30,3 million), respectively.

Current PET/MRI systems are very expensive, only affordable by well-financed health centres. The MindView project aims to develop a new system to be marketed as an upgraded dedicated RF coil to the head examination. This will trigger an expansion of PET/MRI technology around the World. The sensitivity of current PET scanners is of the order of 1% (1,5% in the Siemens mMR). This feature, together with the lack of clinical availability of specific tracers, does not allow the repeated examination of the same patient in a safe way (large radiation dose). The sensitivity of the MindView system will increase at least three fold, allowing a dose reduction and therefore safe longitudinal studies (repeated examinations on the same patient). Moreover, the resolution of commercial clinical PET scanners is of the order of 4-6mm (4mm in the Siemens mMR), which does not allow the visualization of critical brain structures. However, the resolution of the MindView PET scanner will be submilimetric, allowing the visualization of the amygdala and raphe nucleus, critical information in the diagnosis of schizophrenia and depression.

This project also aims to reduce a radiopharmacy lab to a fully automated tabletop mini clean room able to synthesize specific radiopharmaceuticals in monodoses when needed. The mini-clean room concept BLox is a new concept in order to produce PET tracers using novel microfluidic technology. The mini clean room is small in size and each tracer will be produced in a certified and logged clean room environment at each production occasion to reach cGMP-requirements.

Currently, 18FDG is used in most (in 95% of the cases) PET examinations. No specific tracer allowing the study of neurotransmitter pathways are being used regularly for diagnosing mental disorders. In MindView more specific radiopharmaceuticals will be developed and validated for its use in routine examination of schizophrenia and depression. Moreover, innovative infusion protocols, based on continuous injection, will be validated and standardized, allowing the study of neurotransmitter displacements while performing activation paradigms.

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