Investigating exchange, structural disorder, and restriction in gray matter via water and metabolites diffusivity and kurtosis time-dependence.

Water diffusion-weighted MRI is a very powerful tool for probing tissue microstructure, butdisentangling the contribution of compartment-specific structural disorder from cellularrestriction and inter-compartment exchange remains an open challenge. In this work, we usediffusion-weighted MR spectroscopy (dMRS) of water and metabolite as a function of diffusiontimein mouse gray matter to shed light on: i) which of theseconcomitant mechanisms (structural disorder, restriction, and exchange) dominates the MRmeasurements and ii) with which specific signature. We report the diffusion time-dependence ofwater with excellent SNR conditions as provided by dMRS, up to a very long diffusion time (500ms). Water kurtosis decreases with increasing diffusion time, showing the concomitant influenceof both structural disorder and exchange. However, despite the excellent experimentalconditions, we were not able to clearly identify the nature of the structural disorder (i.e.,1D2D/3D short-range disorder). Measurements of purely intracellularmetabolites diffusion time-dependence (up to 500 ms) show opposite behavior to water, withmetabolites kurtosis increasing as a function of diffusion time. We show that this is asignature of diffusion restricted in the intracellular space, from which cellularmicrostructural features such as soma's and cell projections' size can beestimated. Finally, by comparing water and metabolite diffusion time-dependencies, we attemptto disentangle the effect of intra/extracellular exchange and structural disorder of theextracellular space (both impacting water diffusion only). Our results suggest a relativelyshort intra/extracellular exchange time (~1-50 ms) and short-range disorder (still unclear if1D or 2D/3D) most likely coming from the extracellular compartment. This work provides novelinsights to help interpret water diffusion-time dependent measurements in terms of theunderlying microstructure of gray matter and suggests that diffusion-time dependentmeasurements of intracellular metabolites may offer a new way to quantify microstructuralrestrictions in gray matter.