Morphological and Microstructural Changes of the Hippocampus in Early MCI: A Study Utilizing the Alzheimer's Disease Neuroimaging Initiative Database

Abstract

Background and purpose: With the aim of facilitating the early detection of Alzheimer's disease, the Alzheimer's Disease Neuroimaging Initiative proposed two stages based on the memory performance: early mild cognitive impairment (EMCI) and late mild cognitive impairment (LMCI). The current study was designed to investigate structural differences in terms of surface atrophy and microstructural changes of the hippocampus in EMCI and LMCI.

Methods: Hippocampal shape modeling based on progressive template surface deformation was performed on T1-weighted MRI images obtained from 20 cognitive normal (CN) subjects, 17 EMCI patients, and 20 LMCI patients. A template surface in CN was used as a region of interest for diffusion-tensor imaging (DTI) voxel-based morphometry (VBM) analysis. Cluster-wise group comparison was performed based on DTI indices within the hippocampus. Linear regression was performed to identify correlations between DTI metrics and clinical scores.

Results: The hippocampal surface analysis showed significant atrophies in bilateral CA1 regions and the right ventral subiculum in EMCI, in contrast to widespread atrophy in LMCI. DTI VBM analysis showed increased diffusivity in the CA2-CA4 regions in EMCI and additionally in the subiculum region in LMCI. Hippocampal diffusivity was significantly correlated with scores both for the Mini Mental State Examination and on the Modified Alzheimer Disease Assessment Scale cognitive subscale. However, the hippocampal diffusivity did not vary significantly with the fractional anisotropy.

Conclusions: EMCI showed hippocampal surface changes mainly in the CA1 region and ventral subiculum. Diffusivity increased mainly in the CA2-CA4 regions in EMCI, while it decreased throughout the hippocampus in LMCI. Although axial diffusivity showed prominent changes in the right hippocampus in EMCI, future studies need to confirm the presence of this laterality difference. In addition, diffusivity is strongly correlated with the cognitive performance, indicating the possibility of using diffusivity as a biomarker for disease progression.

Keywords: Alzheimer's disease; biomarkers; diffusion-tensor imaging; hippocampus; magnetic resonance imaging; mild cognitive impairment.

Fig. 1. Overall scheme of the analysis. A: T1-weighted images were segmented using Freesurfer to extract the hippocampus. The template model from the normal group was used to construct the group surface model and determine intergroup morphometry differences. B: DTI maps were processed using the TBSS pipeline up to the nonlinear register in an MNI space. Using a surface model of the hippocampus generated from T1-weighted images as a mask, we compared hippocampal diffusivity differences among groups. ADNI: Alzheimer's Disease Neuroimaging Initiative, DTI: diffusion-tensor imaging, FA: fractional anisotropy, FSL: functional MRI of the brain software library, ROI: region of interest, TBSS: Tract-Based Spatial Statistics.

Fig. 2. Hippocampal volumes in each group. Bilateral hippocampal volumes in EMCI were not significantly smaller than those in CN. While the left hippocampal volumes in EMCI were significantly smaller than those in LMCI, they did not differ significantly from those in CN (^*p<0.05, ^†p<0.001). CN: cognitive normal, EMCI: early mild cognitive impairment, LMCI: late mild cognitive impairment.

Fig. 3. Morphometry changes. Delineation of hippocampal subfields in the average template from CN (leftmost). Hippocampal surface analysis showed significant atrophy in bilateral CA1 regions and the right ventral subiculum in EMCI compared to CN, and in bilateral CA1 and CA2–CA4 regions and the subiculum in LMCI (uncorrected p<0.05). CN: cognitive normal, EMCI: early mild cognitive impairment, H: head, LMCI: late mild cognitive impairment, T: tail.

Fig. 4. Microstructural changes in each group. Clusters showing changes in DTI indices: MD (A), AxD (B), and RD (C). All comparisons except those in EMCI and LMCI were corrected for multiple comparisons. A and C: MD and RD were higher in EMCI than in CN in the bilateral CA2–CA4 regions, and higher in LMCI in the bilateral CA2–CA4 and subiculum regions. B: AxD was higher in EMCI than in CN in the right CA2–CA4 regions, and higher in LMCI in the bilateral CA2–CA4 and subiculum regions (purple, MD; red, AxD; blue, RD). A: anterior, AD: Alzheimer's disease, AxD: axial diffusivity, CN: cognitive normal, DTI: diffusion-tensor imaging, EMCI: early mild cognitive impairment, LMCI: late mild cognitive impairment, MD: mean diffusivity, P: posterior, RD: radial diffusivity, S: superior.

Fig. 5. Linear relationships between DTI metrics and clinical scores. Clusters showing linear relationships with DTI indices: MD (A), AxD (B), and RD (C). RD versus MMSE and MADAS-Cog scores (purple, MD; red, AxD; blue, RD). Scatter plots showing the correlations between result clusters and clinical scores (green, EMCI; blue, LMCI; red, AD). A: anterior, AD: Alzheimer's disease, AxD: axial diffusivity, DTI: diffusion-tensor imaging, EMCI: early mild cognitive impairment, LMCI: late mild cognitive impairment, MADAS-Cog: Modified Alzheimer's Disease Assessment Scale-Cognitive subscale, MD: mean diffusivity, MMSE: Mini Mental State Examination, P: posterior, RD: radial diffusivity, S: superior.