Differential vulnerability of hippocampal microstructure in 5xFAD mouse model of Alzheimer’s Disease: A dMRI study

Abstract

AbstractBackgroundHippocampal subfields exhibit differential vulnerabilities to Alzheimer’s disease (AD) associated pathologies. These pathological processes extensively attenuate the structural and functional interconnectivities of the subfields. Abnormal accumulation of beta‐amyloid (Aβ) is considered a primary hallmark of AD. Histopathological studies suggest region‐specific accumulation of Aβ in hippocampal subfields. The aim of the current study is to understand the subfield‐specific in‐vivo microstructural changes in hippocampus due to Aβ load in 2.5 months old 5xFAD mouse model of AD.MethodTwo and a half month old male 5xFAD and age‐matched littermate controls were used in this study. DWI and anatomical images were acquired on a horizontal bore 9.4T Biospec micro‐MRI system equipped with a H1 cryogenic surface coil. 2D T2‐weighted anatomical images were acquired using the following parameters: TE/TR=43.67/7500 ms, voxel size=117x117x250 µm3 and number of slices=20. DWIs were acquired using multi‐shot dual‐spin‐echo EPI sequence using following parameters: TE/TR=34.78/3000 ms, voxel size=117x117x250 µm3, number of slices=20, 3 b‐values (650, 1200 and 2500) s/mm2, 5 b0 per shell, 12 diffusion encoding direction for b=650, 60 for b=1200 and 80 for b=2500 s/mm2. T2‐W images were nonlinearly registered to Badhwar hippocampal atlas. Hippocampal subfields (CA1, CA2, CA3, DG and Subiculum) in atlas space were transformed to individual T2W space and then linearly transformed to DWI space. Multi‐compartment microstructural imaging was performed using Cortical‐NODDI. Volume fraction of isotropic water diffusivity (VFISO) and intracellular volume fraction (VFIC) maps were calculated. The regional mean values (VFIC and VFISO) of individual subfields were extracted and used in general linear model for group‐comparisons.ResultThe results of the study suggest group‐level differences between control and 5xFAD mice in cornu ammonis regions. Compared to 5xFAD, VFIC in littermate control mice was significantly higher in CA1 (p<0.05; d=1.47), CA2 (p<0.05; d=1.11) and CA3 (p<0.05; d=1.54). VFISO in DG was significantly lower in littermate control compared to 5xFAD mice (p<0.05; d=1.31).ConclusionThe study demonstrates the importance of utilizing tissue‐specific microstructural imaging in detecting Aβ associated microstructural alterations in multiple hippocampal subfields. This study demonstrates that Aβ alters the hippocampal microstructure. study also suggests on the differential effect of Aβ pathology on hippocampal microstructure.