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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MICROBRADAM (Advanced MR methods for characterization of microstructural brain damage)

Teaser

Summary

Magnetic resonance imaging (MRI) is a main resource for experimental neuroscience and clinical research. The practical applications of MRI, including diagnostics, are of primary importance. The key features of MRI at the origin of this success include the fact that it is non-invasive and can produce extremely versatile contrast even without external contrast agents.
The former property allows repeated scanning on the same subject without safety concerns. It is a useful feature both to track a pathology or treatment in a single subject, and to develop new techniques.
The versatility of contrast is related to the fact that nuclear spins can be manipulated to make MR signal sensitive 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 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 developed of a set of advanced MR techniques for the characterization of microstructural damage in some key applications, from animal models to pilot clinical studies. Albeit different pathophysiologically, many brain diseases share two common needs: the need of quantitative tools for characterizing the specific mechanisms underlying tissue damage, and the need of diagnostic tools that can: 1) identify the pathology at its earliest stages before manifestation of severe clinical symptoms, and 2) assess even subtle efficacy of experimental treatments.
Myelin sheath breakdown is the main form of microstructural damage shared by many neurological diseases. Quantification of myelin integrity is thus critical for the assessment of a variety of neurological diseases including Multiple Sclerosis (MS). The techniques we developed, based on a phenomenon called â€œRelaxation Along a Fictitious Fieldâ€ (RAFF), showed a great sensitivity to demyelination. While we did not reach yet the endpoint of truly â€œtissue-composition-specificâ€ MRI, the new techniques are a significant improvement that add information to the multiparametric approach needed to personalize treatments and care of the patients.

Work performed

We developed advanced MRI approaches based on non-adiabatic relaxation called RAFFn (RAFF of rank n), studying in particular the ranks n=4 and 5. These are especially sensitive to slow molecular motion, and we showed that they are sensitive to 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.
We developed also 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 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, and can be used in therapeutic interventions, for instance in Deep Brain Stimulation (DBS) in Parkinsonâ€™s and in other neurodegenerative diseases.
Main results we obtained include a study on semantic network in Alzheimer â€™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. We also studied the nature of impulsive control disorder in Parkinsonâ€™s disease, which greatly exceed the previously envisioned dopaminergic pathways as the only culprit. Finally, we showed that our innovative approaches to DBS have the potential to improve the patientâ€™s treatment, being easily tailored to the needs of each single patient.
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.

Final results

The basic effectiveness in PD, MS, iRBD, AD was tested in this study. An 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. We are actively testing our techniques on larger populations, to assess the feasibility of their application in clinical setting. 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, 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 improve single patients care in the clinical routine.