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MICROBRADAM Report Summary

Project ID: 691110
Funded under: H2020-EU.1.3.3.

Periodic Reporting for period 1 - MICROBRADAM (Advanced MR methods for characterization of microstructural brain damage)

Reporting period: 2015-11-01 to 2017-10-31

Summary of the context and overall objectives of the project

Experimental neuroscience and clinical research are only two of the main research fields where magnetic resonance imaging (MRI) is considered as a main resource. The practical applications of MRI, including diagnostics, are of primary importance. The key features of MRI that caused this success include the fact that it is non-invasive and can produce extremely versatile contrast even without external contrast agents. This property is related to the proper manipulation of NMR signal that can be sensitized to several biophysical and biological phenomena. NMR applications are continuously evolving, and there is opportunity for many technological advances that can be easily exploited as MRI contrasts in clinical applications.
Microstructural damage is indeed a common, key point for the characterization and understanding of many serious neurological and psychiatric diseases and disorders, including neurodegenerative diseases. In this project we are developing of a set of advanced MR techniques for the characterization of microstructural damage in some key applications, on the validation of these techniques on animal models, and finally on the translation of these techniques to pilot clinical studies. Albeit different pathophysiologically, many brain diseases share two common needs: the need of proper, quantitative tools for characterizing the specific mechanisms underlying tissue damage, and the need of diagnostic tools that can identify the pathology at its earliest stages before manifestation of severe clinical symptoms and can assess even subtle efficacy of experimental treatments.
The main form of microstructural damage shared by many neurological diseases is related to myelin sheath breakdown. Quantification of myelin is thus critical for the assessment of a variety of neurological diseases including Multiple Sclerosis (MS). The techniques we are developing have a potential specific sensitivity to demyelination. Truly “tissue-composition-specific” MRI would be a tremendous advance, as it would allow monitoring of the effect of treatments geared toward specific pathologic processes, as well as help clarify the pathophysiologic basis of myelin-related diseases.
Primary objectives of our research are to assess in living rodents if the MRI techniques we are developing are able to assess the myelin content, used alone, or in conjunction with conventional MR approaches, and to extend these results to humans.
Secondary aims will be to develop appropriate multiparametric processing approaches, capable to improve the quantitative information that can be extracted from the data, and to assess if our techniques are sensitive to dynamic changes, i.e. if they are capable to detect demyelination and remyelination.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first half of this project we developed advanced MRI approaches based on non-adiabatic relaxation called RAFFn (Relaxation Along a Fictitious Field of rank n), studying in particular the ranks n=4 and 5. These are especially sensitive to slow molecular motion, expected to be modulated by myelin damage. We measured myelin content and integrity in the normal brain and in complex pathologies in rodents. We obtained very high correlation between relaxation and myelin content as assessed by quantitative histology. Importantly, the correlation we obtained is much improved compared to what can be achieved with conventional MRI approaches. Sensitive detection of demyelination was possible in various brain areas, with different tissutal properties.
In parallel with the development of these advanced structural MRI techniques, we are developing functional imaging methods, in order to identify the functional correlates of microstructural damage. Our efforts were focalized in two fields: steady state functional connectivity and neuromodulation. Functional connectivity is an approach that quantifies the network behavior of the brain, and is especially attractive for pathologies because it does not assume any specific area of functional response, but characterizes the cortex as a whole. Neuromodulation, that is a byproduct of some of the MRI techniques we developed is important as well, because allows isolating specific neural processes.
Main results we obtained include a study on semantic network in Alzheimer’s Disease (AD), that showed that in mild AD brain regions belonging to the semantic control network are abnormally connected not only within the network, but also to other areas known to be critical for language processing.
Given the complex features of microstructural damage, it is likely that a multiparametric integration of different metrics is needed, where the new approaches we propose are intended to complement other quantitative techniques. MRI in itself lends naturally towards multiparametric studies, because it can produce images sensitized to multiple contrast mechanisms, as described above. MRI can also be combined with compatible approaches, including PET based molecular imaging, electrophysiological measurements and neuromodulation. In this project, we implemented an appropriate set of processing tools to combine different kind of information. Main results obtained with this approach are related to Parkinson Disease (PD) and the associate idiopathic REM sleep behavior disorder (iRBD). We were able to show that rotating frame relaxation methods, along with functional connectivity measures, are valuable to characterize iRBD and PD subjects, and with proper validation in larger cohorts these approaches may provide pathological signatures of iRBD and PD.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The basic effectiveness in PD, MS, iRBD, AD is being tested by this study, and unprecedented sensitivity to detect demyelination in vivo and non invasively has been already proven. We expect that the systematic transition of the newly developed techniques to human applications in a clinical environment will offer significant advantage also in other pathologies not directly addressed by this project. Therefore, insights gained from this project may ultimately have a significant impact on reducing the morbidity associated with neurodegeneration in general. Any new tools available for early detection and therapy assessment in neurodegeneration has a great potential impact, given the enormous personal and public health burden of neurodegenerative diseases.
Information obtained from this project is expected to improve patient care through early disease detection and better assessment of disease progression or treatment in the future. In particular, we believe that the information gained in this investigation will be important in developing new ways to monitor for changes in the brain that occur in neurodegeneration in general.
We envisage that this process will happen in two stages. A first stage, that is already occurring, is the diffusion of the advanced methods we are developing to an increasingly wide community of neuroscientists. The availability of such sensitive tools to characterize microstructural brain damage and the relevant functional counterpart is improving the quality of the research of the involved research teams, and we committed ourselves to widen as far as possible the dissemination of our approaches.
In a second, long term stage our techniques (together with hardware improvements of the MRI instrumentation) have the potential to be applied to single patients in the clinical routine, to improve and personalize the diagnosis and the treatments.

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