Characterizing the human hippocampus in aging and Alzheimer's disease using a computational atlas derived from ex vivo MRI and histology

Abstract

Although the hippocampus is one of the most studied structures in the human brain, limited quantitative data exist on its 3D organization, anatomical variability, and effects of disease on its subregions. Histological studies provide restricted reference information due to their 2D nature. In this paper, high-resolution (∼200 × 200 × 200 μm³) ex vivo MRI scans of 31 human hippocampal specimens are combined using a groupwise diffeomorphic registration approach into a 3D probabilistic atlas that captures average anatomy and anatomic variability of hippocampal subfields. Serial histological imaging in 9 of the 31 specimens was used to label hippocampal subfields in the atlas based on cytoarchitecture. Specimens were obtained from autopsies in patients with a clinical diagnosis of Alzheimer's disease (AD; 9 subjects, 13 hemispheres), of other dementia (nine subjects, nine hemispheres), and in subjects without dementia (seven subjects, nine hemispheres), and morphometric analysis was performed in atlas space to measure effects of age and AD on hippocampal subfields. Disproportional involvement of the cornu ammonis (CA) 1 subfield and stratum radiatum lacunosum moleculare was found in AD, with lesser involvement of the dentate gyrus and CA2/3 subfields. An association with age was found for the dentate gyrus and, to a lesser extent, for CA1. Three-dimensional patterns of variability and disease and aging effects discovered via the ex vivo hippocampus atlas provide information highly relevant to the active field of in vivo hippocampal subfield imaging.

Keywords: Alzheimer’s disease; computational anatomy; ex vivo MRI; hippocampal subfields; histology.

Fig. 1.

The hippocampus atlas obtained by groupwise registration of the MRI scans of 31 ex vivo specimens and its hippocampal subfield segmentation derived from serial histology in nine specimens. The atlas represents the average hippocampal anatomy.

Fig. 2.

Statistical maps of regional thickness difference between AD and NC subjects, covarying for age and sex. Separate maps are generated for the dentate gyrus, stratum radiatum lacunosum moleculare (SRLM), and outer gray matter layers of the hippocampus. The maps are in atlas space, viewed from the superior (Top) and inferior (Bottom). Locations that survive the false discovery rate correction at the α = 0.05 threshold are demarcated by a black outline.