Final Report Summary - INCELL (Exploring brain intracellular space using diffusion-weighted NMR spectroscopy in vivo) The goal of the INCELL project was to measure, using diffusion-weighted magnetic resonance (NMR) spectroscopy in vivo, the diffusion of brain intracellular metabolites at very different time scales, to probe and quantify cells’ average structural properties over very different spatial scales, from intracellular viscosity to cell size.Advanced NMR spectroscopy methods have been developed, allowing the measurement of metabolites diffusion over an unprecedented time-window, from ~0.2 milliseconds to ~2 seconds. We have introduced original modeling strategies based on numerical simulations to analyze diffusion data in terms of underlying cell structure, and have given the first proof of concept of the feasibility to extract quantitative information about neuronal and astrocytic morphology in the rodent brain. This validated the main hypothesis of the project, namely the possibility to interpret the diffusion of intracellular metabolites primarily in terms of cellular structure, and to quantitatively derive relevant structural parameters by adequate modeling of diffusion data at different scales.Developed methods have then been applied in a mouse model of astrocyte reactivity, a process which occurs during neuroinflammation, including in some neurodegenerative diseases, and which is known to result in astrocytic hypertrophy. We have been able to measure specific alterations of astrocytic metabolite diffusion that we could quantitatively link to alterations of astrocytic morphology (increased diameter and length of astrocytic processes), as extracted from diffusion modeling and validated by confocal microscopy ex vivo. In the end, the project opened unique possibilities to non-invasively assess cell-specific morphological alterations in the brain. Perspectives include transfer to clinical MRI scanners to perform similar measurements in humans, and application to neurodegenerative diseases.
