In vivo Mapping of Cellular Resolution Neuropathology in Brain Ischemia by Diffusion MRI

Non-invasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent developments in diffusion MRI have produced new tools for examining tissue microstructure at a level well below the imaging resolution. Here, we report the use of diffusion time (t)-dependent diffusion kurtosis imaging (tDKI) to simultaneously assess the morphology and transmembrane permeability of cells and their processes in the context of pathological changes in hypoxic-ischemic brain (HI) injury. Through Monte Carlo simulations and cell culture organoid imaging, we demonstrate feasibility in measuring effective size and permeability changes based on the peak and tail of tDKI curves. In a mouse model of HI, in vivo imaging at 11.7T detects a marked shift of the tDKI peak to longer t in brain edema, suggesting swelling and beading associated with the astrocytic processes and neuronal neurites. Furthermore, we observed a faster decrease of the tDKI tail in injured brain regions, reflecting increased membrane permeability that was associated with upregulated water exchange upon astrocyte activation at acute stage as well as necrosis with disrupted membrane integrity at subacute stage. Such information, unavailable with conventional diffusion MRI at a single t, can predict salvageable tissues. For a proof-of-concept, tDKI at 3T on an ischemic stroke patient suggested increased membrane permeability in the stroke region. This work therefore demonstrates the potential of tDKI for in vivo detection of the pathological changes in microstructural morphology and transmembrane permeability after ischemic injury using a clinically translatable protocol.