L'imagerie IRM permet d'observer les principaux faisceaux de fibres de substance blanche dans le cerveau. Cette imagerie offre de nombreuses applications potentielles pour mieux comprendre le développement du cerveau sain et pathologique ou pour étudier l'impact de substances thérapeutiques. Pour observer ces fibres, il faut combiner une acquisition IRM bien maitrisée aujourd'hui avec une procédure de traitement de données qui est encore le sujet de différents projets de recherche. Pour caractériser ces fibres qui ne font que quelques microns de diamètre, il faut porter la résolution spatiale de l'IRM au-delà de la résolution spatiale d'acquisition. Pour obtenir cette super-résolution, il a été proposé de combiner une modélisation biophysique du signal avec différentes mesures du signal IRM. L'ensemble permet d'accéder par exemple à des mesures du diamètre axonal, comme par exemple l'approche AxCaliber (Assaf 2008). Un des intérêts de cette mesure est qu'elle est corrélée à la vitesse de conduction des signaux électriques (Horowitz 2015). Ces développements méthodologiques sont principalement réalisés chez l'homme. Pourtant, de nombreux modèles animaux sont utilisés pour comprendre le cerveau sain et pathologique. Dans le cadre d'une collaboration entre l'équipe UNIRS de Neurospin (Cyril Poupon) et l'équipe 5 du GIN (Emmanuel Barbier), nous avons initié des travaux pour porter chez la souris les outils actuellement employés chez l'homme. / Magnetic resonance imaging (MRI) allows the observation of the major white matter fiber tracts in the brain. It can thus be used in many applications to have a better understanding of the development of healthy and pathological brains and to study the effect of potential therapeutic treatments. In order to observe these fibers, one must combine a today well-controlled MRI acquisition with a data processing procedure that is still under investigation for many research projects. To characterize those fibers whose diameters are only a few microns wide, the MRI spatial resolution must be raised beyond the spatial resolution of the acquisition. This super-resolution achievement can be obtained by combining biophysical models with several measures of the MRI signal. Together, one can gain access to axon diameter measures for example, as was done by Assaf in 2008 (AxCaliber approach). One of the interests of this measure is its correlation with the conduction velocity of the electric signals (Horowitz 2015). These methodological developments are mainly done in human research. However, many animal models are used to understand the healthy as well as the pathological brains. In the context of a collaboration between team UNIRS of NeuroSpin (Cyril Poupon) and team 5 of GIN (Grenoble Institute of Neuroscience) (Emmanuel Barbier), we have initiated the transfer for the mouse of the tools currently used for human.

Parkinson’s disease patients present with the highest risk of dementia development. The thalamus, integral to several functions and behaviours is involved in the pathophysiology of Parkinson’s disease. The aim of this thesis was to determine if anatomical abnormalities in the thalamus are associated with the development of dementia in Parkinson’s disease. We examined the thalamus using macro and microstructural techniques and the white matter pathways that connect the thalamus with areas of the surrounding cortex using diffusion tensor imaging (DTI) based tractography. T1-weighted magnetic resonance and DT images were collected in 56 Parkinson’s disease patients with no cognitive impairment, 19 patients with mild cognitive impairment, 17 patients with dementia and 25 healthy individuals who acted as control subjects. An established automated segmentation procedure (FIRST FSL) was used to delineate the thalamus and a modified k-means clustering algorithm applied to segment the thalamus into clusters assumed to represent thalamic nuclei. Fibre tracts were determined using DTI probabilistic tracking methods available in FIRST. Microstructural integrity was quantified by fractional anisotropy and mean diffusivity (MD) DTI measures. Results show that microstructural measures of thalamic integrity are more sensitive to cognitive dysfunction in PD than macrostructural measures. For the first time we showed a progressive worsening of cellular integrity (MD) in the groups who had greater levels of cognitive dysfunction. Thalamic degeneration was regionally specific and most advanced in the limbic thalamic nuclei which influenced executive function and attention, areas of cognition that are known to be affected in the earliest stages of PD. The integrity of the fibre tracts corresponding to these thalamic regions was also compromised. Degeneration of fibre tracts was most evident in the dementia group, indicating that they may be more protected against Lewy pathology than the nuclei of the thalamus. Our findings confirm previous histological, animal and lesion studies and provide a reliable estimate of cortical degeneration in PD that can be applied non-invasively and in vivo. A longitudinal study is needed to monitor the progression of cognitive decline in PD but we have provided the basis for further investigation into the predictive validity of thalamic degeneration for cognitive dysfunction. In the future, the microstructural changes of the thalamus could be used as biomarkers for the identification of individuals with a higher risk for dementia development and for the longitudinal monitoring of any interventions into cognitive decline.