"Alterations of the intracellular space, including intracellular protein accumulation, organelle and cytoskeleton dislocation, and modifications in cell shape, are an early hallmark of many neurodegenerative processes. The ability to assess and quantify these alterations non-invasively would be of tremendous interest, not only in a clinical context, but also for preclinical research. However, no tool currently exists allowing such measurements.Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) gives access to the apparent diffusion coefficient (ADC) of brain metabolites in vivo, which is related to their average quadratic displacement. Since metabolites are purely intracellular, their ADC is solely governed by the properties of the intracellular space. The dependency of the ADC on the delay during which displacement is measured (the “diffusion time” Td) tells how metabolite motion deviates from free diffusion, which can in theory help untangle and quantify the different factors governing motion.So far, DW-MRS has only been performed in a limited number of studies, for Td ranging from ~10 to ~100 milliseconds, and has not yet demonstrated its ability to quantitatively assess the intracellular space. In the present work, we will develop cutting-edge DW-MRS methods to probe brain metabolite motion for Td varying over several orders of magnitude (from ~0.1 milliseconds to ~10 seconds). The dependency of the ADC over Td will provide unique insights about the mechanisms governing metabolite motion at very different scales. Data will be modeled to quantitatively extract parameters such as the intracellular viscosity, the size of intracellular structures, and cell shape and size. Estimated parameter values will be compared to values derived from other techniques, such as microscopy. Finally, developed methods will be used to investigate early alterations of the intracellular space in animal models of neurodegeneration."