Layer-specific microstructural patterns of anterior hippocampus in Alzheimer's disease with ex vivo diffusion MRI at 14.1 T

Abstract

High-resolution ex vivo diffusion MRI (dMRI) can provide exquisite mesoscopic details and microstructural information of the human brain. Microstructural pattern of the anterior part of human hippocampus, however, has not been well elucidated with ex vivo dMRI, either in normal or disease conditions. The present study collected high-resolution (0.1 mm isotropic) dMRI of post-mortem anterior hippocampal tissues from four Alzheimer's diseases (AD), three primary age-related tauopathy (PART), and three healthy control (HC) brains on a 14.1 T spectrometer. We evaluated how AD affected dMRI-based microstructural features in different layers and subfields of anterior hippocampus. In the HC samples, we found higher anisotropy, lower diffusivity, and more streamlines in the layers within cornu ammonis (CA) than those within dentate gyrus (DG). Comparisons between disease groups showed that (1) anisotropy measurements in the CA layers of AD, especially stratum lacunosum (SL) and stratum radiatum (SR), had higher regional variability than the other two groups; (2) streamline density in the DG layers showed a gradually increased variance from HC to PART to AD; (3) AD also showed the higher variability in terms of inter-layer connectivity than HC or PART. Moreover, voxelwise correlation analysis between the coregistered dMRI and histopathology images revealed significant correlations between dMRI measurements and the contents of amyloid beta (Aβ)/tau protein in specific layers of AD samples. These findings may reflect layer-specific microstructural characteristics in different hippocampal subfields at the mesoscopic resolution, which were associated with protein deposition in the anterior hippocampus of AD patients.

Keywords: Alzheimer's disease; anterior hippocampus; connectivity; diffusion MRI; histology; mesoscale.

FIGURE 1

Cross‐sectional displays of anterior hippocampus segmentations for all samples in coronal view. PO, polymorphic layer; SG, stratum granulosum; SL, stratum lacunosum; SM, stratum moleculare; SO, stratum oriens; SP, stratum pyramidale; SR, stratum radiatum

FIGURE 2

dMRI‐based microstructural maps and tractography of anterior hippocampus in a control sample. (a) and (b) represent the FA and MD maps from DTI analysis; (d) and (e) represent the nQA and ISO maps from GQI analysis, and zoom‐in view of the hippocampus (white rectangle) reveal the six hippocampal layers (black arrows); (c) and (f) show the directional encoded color maps and QA‐based tractography, respectively, where the white stars indicate the radial fibers that run perpendicular to the proximal‐distal axis (white arrows) and yellow stars indicate the fibers running along the proximal‐distal axis. DTI, diffusion tensor imaging; FA, fractional anisotropy; GQI, generalized q‐sampling imaging; ISO, isotropic diffusivity; MD, mean diffusivity; nQA, normalized quantitative anisotropy

FIGURE 3

Layer‐specific pattern of the dMRI‐based microstructural indices and connectivity in three control samples. (a) the morphological differences in anterior hippocampus among three control samples. Red arrows point to the folding structures. (b) The dMRI indices, the number of streamlines, and streamline density averaged from the three control samples in each layer. (c) Structural connectivity matrix between the seven layers for each control case. The areas with pink rectangle indicated stronger connectivity among the CA layers than those among the DG layers or inter‐subfield connectivity (off‐diagonals). Streamline density = streamlines/volume/100. CA, cornu ammonis; DG, dentate gyrus; FA, fractional anisotropy; ISO, isotropic diffusivity; MD, mean diffusivity; nQA, normalized quantitative anisotropy

FIGURE 4

Comparison between DTI‐ and GQI‐based fiber orientation distribution maps (a) tractography (b) in anterior hippocampus of a control sample. The crossing fibers (white arrows) in hippocampal region (white rectangle) consist of Mossy fiber pathway (unmyelinated axons from granule cells in DG to modulatory hilar mossy cells in CA3), and the axons of hippocampal pyramidal neurons that run perpendicular to it. DG, dentate gyrus; DTI, diffusion tensor imaging; GQI, generalized q‐sampling imaging

FIGURE 5

Comparisons of the dMRI‐based microstructural indices among three groups. (a) Coronal view of the FA, MD, nQA, and ISO maps of a control, PART and AD hippocampus. (b) Layer‐specific patterns of MD, FA, nQA, and ISO measurements in all samples. Variabilities of FA and nQA measurements were both higher in the SL and SR layers of the AD samples than those of HC and PART (black rectangle). Each circle represents an individual sample; blue, green, and red represent the HC, PART, and AD group, respectively; fork and square markers reflect the group mean and standard deviation, respectively. AD, Alzheimer's diseases; FA, fractional anisotropy; HC, healthy control; ISO, isotropic diffusivity; MD, mean diffusivity; nQA, normalized quantitative anisotropy; PART, primary age‐related tauopathy; SL, stratum lacunosum; SR, stratum radiatum

FIGURE 6

Layer‐specific patterns of the number of streamline and streamline density in each hippocampal layer (a, b) and the density from each of the seed layer to the other layers (c–i) for all samples. Variabilities were higher in the connections from three DG layers to the other layers of the AD samples than those of HC and PART (black rectangle). AD, Alzheimer's diseases; DG, dentate gyrus; HC, healthy control; PART, primary age‐related tauopathy

FIGURE 7

Voxel‐wise correlations between the normalized Aβ and tau intensities and the dMRI indices in AD1. Only the layers showing significant histology‐MRI correlations (p < .001) were plotted. AD, Alzheimer's disease; ISO, isotropic diffusion; FA, fractional anisotropy; MD, mean diffusion; nQA, normalized quantitative anisotropy; SL, stratum lacunosum; SM, stratum moleculare; SP, stratum pyramidale; SR, stratum radiatum