Characterizing the microstructural transition at the gray matter-white matter interface: Implementation and demonstration of age-associated differences

Background: The cortical gray matter-white matter interface (GWI) is a natural transition zone where the composition of brain tissue abruptly changes and is a location for pathologic change in brain disorders. While diffusion magnetic resonance imaging (dMRI) is a reliable and well-established technique to characterize brain microstructure, the GWI is difficult to assess with dMRI due to partial volume effects and is normally excluded from such studies. Methods: In this study, we introduce an approach to characterize the dMRI microstructural profile across the GWI and to assess the sharpness of the microstructural transition from cortical gray matter (GM) to white matter (WM). This analysis includes cross-sectional data from a total of 146 participants (18-91 years; mean age: 52.4 (SD 21.4); 83 (57 %) female) enrolled in two normative lifespan cohorts at Albert Einstein College of Medicine from 2019 to 2023. We compute the aggregate GWI slope for each parameter, across each of 6 brain regions (cingulate, frontal, occipital, orbitofrontal, parietal, and temporal) for each participant. The association of GWI slope in each region with age was assessed using a linear model, with biological sex as a covariate. Results: We demonstrate this method captures an inherent change in fractional anisotropy (FA), axial diffusivity (AD), orientation dispersion index (ODI) and intracellular volume fraction (ICVF) across the GWI that is characterized by small variance. We identified statistically significant associations of FA slope with age in all regions (p < 0.002 for all analyses), with FA slope magnitude inversely associated with higher age. Similar statistically significant age-related associations were found for AD slope in cingulate, occipital, and temporal regions, for ODI slope in parietal and occipital regions, and for ICVF slope in frontal, orbitofrontal, parietal, and temporal regions. Conclusion: The inverse association of slope magnitude with age indicates loss of the sharp GWI transition in aging, which is consistent with processes such as dendritic pruning, axonal degeneration, and inflammation. This method overcomes techniques issues related to interrogating the GWI. Beyond characterizing normal aging, it could be applied to explore pathological effects at this crucial, yet under-researched region.