The direction-dependence of apparent water exchange rate in human white matter

Transmembrane water exchange is a potential biomarker in the diagnosis and understanding of cancers, brain disorders, and other diseases. Filter-exchange imaging (FEXI), a special case of diffusion exchange spectroscopy adapted for clinical applications, has the potential to reveal different physiological water exchange processes. However, it is still controversial whether modulating the diffusion encoding gradient direction can affect the apparent exchange rate (AXR) measurements of FEXI in white matter (WM) where water diffusion shows strong anisotropy. In this study, we explored the diffusion-encoding direction dependence of FEXI in human brain white matter by performing FEXI with 20 diffusion-encoding directions on a clinical 3T scanner in-vivo. The results show that the AXR values measured when the gradients are perpendicular to the fiber orientation (0.77 +/- 0.13 s - 1 , mean +/- standard deviation of all the subjects) are significantly larger than the AXR estimates when the gradients are parallel to the fiber orientation (0.33 +/- 0.14 s - 1 , p &amp;lt; 0.001) in WM voxels with coherently-orientated fibers. In addition, no significant correlation is found between AXRs measured along these two directions, indicating that they are measuring different water exchange processes. Whats more, only the perpendicular AXR rather than the parallel AXR shows dependence on axonal diameter, indicating that the perpendicular AXR might reflect transmembrane water exchange between intra-axonal and extra-cellular spaces. Further finite difference (FD) simulations having three water compartments (intra-axonal, intra-glial, and extra-cellular spaces) to mimic WM micro-environments also suggest that the perpendicular AXR is more sensitive to the axonal water transmembrane exchange than parallel AXR. Taken together, our results show that AXR measured along different directions could be utilized to probe different water exchange processes in WM.Funding Agencies|National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [81873894, 82111530201]; Natural Science Foundation of Zhejiang Province, ChinaNatural Science Foundation of Zhejiang Province [LR20H180001]; MOE Frontier Science Center for Brain Science &amp; Brain-Machine Integration, Zhejiang University; Swedish Foundation for International Cooperation in Research and Higher Education (STINT)</p