Age‐Related Alterations in Hippocampal Microstructure Quantified Using High‐Gradient Diffusion <scp>MRI</scp> ( <scp>dMRI</scp> ) in an Unfolded Hippocampal Space

The hippocampus, a brain region critical for memory, undergoes significant age-related changes at both the macroscopic and microstructural levels. This study investigates these changes using high-gradient diffusion MRI (dMRI) data analyzed in an unfolded hippocampal space. We applied the Soma and Neurite Density Imaging (SANDI) model to quantify microstructural alterations in 72 cognitively healthy participants aged 19-85 years, scanned on a 3 T Connectome MRI scanner with a maximum gradient strength of 300 mT/m. By combining SANDI with a super-resolution algorithm and the HippUnfold toolbox, we achieved high spatial fidelity in our analysis. We observed significant age-related reductions in soma fraction and soma radius, particularly in the subiculum and dentate gyrus, alongside increases in extracellular diffusivity and extracellular fraction, indicating a decline in cellular density and structural integrity. These microstructural changes occur alongside macroscopic alterations such as reduced hippocampal volume and cortical thickness, decreased gyrification, and increased curvature in specific subfields. The spatial correlations between microstructural and macroscopic metrics across the unfolded hippocampal space are weak, both in their mean values and in how they change with age. Our findings suggest that SANDI metrics provide sensitive and complementary information to traditional structural measures, offering new insights into the microstructural underpinnings of hippocampal aging. This study highlights the potential of advanced dMRI techniques to detect subtle age-related changes in hippocampal microstructure, which may contribute to our understanding of aging and its impact on memory and cognition.