Micro-MRI study of cerebral aging: ex vivo detection of hippocampal subfield reorganization, microhemorrhages and amyloid plaques in mouse lemur primates

Abstract

Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 µm in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages.

Figure 1. resolution MR images of the mouse lemur brain at 7T.

1: corpus callosum; 2: caudate nucleus; 3: septal nuclei; 4: thalamic medullary stria; 5: fornix; 6: lenticular nucleus; 7: optic chiasm; 8: hippocampal fimbria; 9: thalamus; 10: external medullary lamina; 11: Forel's field; 12: mamillo-thalamic tract; 13: cerebral peduncle; 14: optic tract; 15: hippocampus; 16: lateral geniculate body; 17: median lemniscus; 18: posterior commissure; 19: central grey matter; 20: substantia nigra; 21: medial geniculate nucleus; 22: central interpedoncular nucleus; 23: dentate gyrus. Based on .

Figure 2. Analysis of hippocampal subfield volumes.

(A) Segmentation of the hippocampus, divided into the dentate gyrus and the extended Ammon's horn (includes CA1, CA2, CA3, CA4 and subiculum), based on the mouse lemur brain atlas . No correlation was found between age and total hippocampal volume (B), however, we observed a significant decrease with age of the normalized volume of the extended Ammon's horn (C), and a significant increase with age of the normalized volume of the dentate gyrus (D). (E–F) 3D views of hippocampal subfields in one young (E) and one old animal (F), showing the increased volume of the dentate gyrus and decreased volume of the Ammon's horn in the aged lemur as compared to the young one.

Figure 3. Detection of cortical and hippocampal black dots.

(A) Example of the black dots detected in the cortex of mouse lemurs on MR images. (B) The number of black dots in each animal was significantly correlated with age (p<0.005). In one animal, some black dots visible on MR images (C) matched the location of amyloid deposits detected by Abeta staining (D, 4G8 staining, white circles). The level of iron within amyloid deposits was similar or slightly higher than in the surrounding parenchyma (E, Perls-DAB staining). In animals without amyloid deposition, the location of black spots on MR images (F, arrows) corresponded to focal area of microhemorrhages detected by Perls staining (G, arrows).