Microstructural alterations of human medial temporal lobe in dementia: volumetric and DTI findings correlate with cell number and neuropathology

Volumetric and diffusion tensor imaging (DTI) alterations in medial temporal lobe (MTL) regions are consistently reported in Alzheimer's disease (AD). However, their biological basis remains poorly understood. We combined Magnetic Resonance Imaging (MRI) metrics with cellular quantification and neuropathological burden assessment to investigate microstructural substrates underlying MTL imaging alterations in human donors with known cognitive and neuropathological status. Absolute cell numbers were quantified in a cohort of 54 brain donors using the isotropic fractionator, and postmortem MRI was performed on a subset of 18 fixed brain hemispheres. To assess microstructural brain alterations associated with disease progression, in vivo volumetric and DTI metrics were analyzed in 39 cognitively unimpaired controls (CU), 31 individuals with mild cognitive impairment (MCI), and 14 patients with clinical AD dementia. In the postmortem cohort, MTL diffusivity metrics showed moderate negative correlations with total cell numbers. Mean, axial, and radial diffusivity positively correlated with Braak stage, whereas fractional anisotropy (FA) correlated negatively with CERAD score, linking diffusion alterations to AD-related pathology. In vivo MTL analyses revealed increased mean, axial, and radial diffusivity, and reduced FA in AD patients compared with both CU and MCI individuals. The MCI group exhibited intermediate alterations in diffusivity. Differences between in vivo and postmortem diffusion values were consistent with tissue fixation, temperature, and variations in acquisition protocols. Our findings suggest that diffusion MRI alterations in the MTL are associated with reduced cellularity and neuropathological burden, supporting the biological relevance of DTI metrics as markers of microstructural degeneration in AD.