High-Resolution Fluid-Suppressed Diffusion Tractography of the Fornix Across the Healthy Lifespan and Deviations in Multiple Sclerosis

Abstract Diffusion tensor imaging (DTI) can infer microstructural changes in white matter tracts like the fornix (main efferent tract of the hippocampus), where there is limited knowledge on typical changes with age from childhood through adulthood, and on whether DTI deviations in multiple sclerosis (MS) are consistent across the lifespan. The objectives are to determine fornix DTI age relationships in healthy controls and characterize DTI deviations in MS. High-resolution, fluid-suppressed DTI tractography quantified fornix volume and DTI parameters (fractional anisotropy - FA; mean, axial, radial diffusivity - MD, AD, RD) in 103 healthy controls (12-65 years) and 42 MS participants (13-63 years). Other brain volumes were measured on T1-weighted MPRAGE. All parameters were assessed for age trajectories, compared between groups, and correlated to clinical/cognitive assessments in MS. Control fornix volume increased markedly (~1.7x) from 12 to 33 years and then declined to a similar extent by 65 years, while MD, AD, and RD showed U-shaped changes with minima ~30-33 years; conversely, FA showed no age relationship. MS fornix volume followed a similar age trend, but remained below controls at all ages and was proportionally reduced (-29%) more than all other brain volumes. In contrast, age relationships of MD, AD, and RD were lost due to similarly higher diffusivity in MS over all ages and FA was below controls across all ages. MS fornix volume/diffusion metrics correlated with various clinical/cognitive scores. Fluid-suppressed, high-resolution diffusion tractography showed nonlinear changes of the fornix in controls over the observed lifespan and early deviations in MS, consistent across age, suggesting it is an early target of injury.