Gray Matter Atrophy in Amnestic Mild Cognitive Impairment: A Voxel-Based Meta-Analysis

Abstract

Background: Voxel-based morphometry (VBM) has been widely used to investigate structural alterations in amnesia mild cognitive impairment (aMCI). However, inconsistent results have hindered our understanding of the exact neuropathology related to aMCI. Objectives: Our aim was to systematically review the literature reporting VBM on aMCI to elucidate consistent gray matter alterations, their functional characterization, and corresponding co-activation patterns. Methods: The PubMed, Web of Science, and EMBASE databases were searched for VBM studies on aMCI published from inception up to June 2020. Peak coordinates were extracted from clusters that showed significant gray matter differences between aMCI patients and healthy controls (HC). Meta-analysis was performed using seed-based d mapping with the permutation of subject images (SDM-PSI), a newly improved meta-analytic method. Functional characterization and task-based co-activation patterns using the BrainMap database were performed on significant clusters to explore their functional roles. Finally, VBM was performed based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset to further support the findings. Results: A total of 31 studies with 681 aMCI patients and 837 HC were included in this systematic review. The aMCI group showed significant gray matter atrophy in the left amygdala and right hippocampus, which was consistent with results from the ADNI dataset. Functional characterization revealed that these regions were mainly associated with emotion, cognition, and perception. Further, meta-regression analysis demonstrated that gray matter atrophy in the left inferior frontal gyrus and the left angular gyrus was significantly associated with cognitive impairment in the aMCI group. Conclusions: The findings of gray matter atrophy in the left amygdala and right hippocampus are highly consistent and robust, and not only offer a better understanding of the underlying neuropathology but also provide accurate potential biomarkers for aMCI.

Keywords: amnestic mild cognitive impairment; gray matter volume; meta-analysis; seed-based d mapping; voxel-based morphometry.

Figure 1

Flow diagram of inclusion and exclusion process of selected articles of VBM studies in patients with aMCI. aMCI, amnestic mild cognitive impairment.

Figure 2

Regions showing reduced gray matter in aMCI patients.

Figure 3

Funnel plot of effect size of left amygdala (A) and right hippocampus (B).

Figure 4

Meta-regression results showing an association between MMSE and gray matter volume in the aMCI group, in the left inferior frontal gyrus (A), left inferior frontal gyrus (B), and left angular gyrus (C). MMSE, mini-mental state examination.

Figure 5

Functional connectivity and characterization. (A) Left amygdala. (B) Co-activation connectivity analysis for left amygdala. (C) Functional characterization of left amygdala. (D) Right hippocampus. (E) Co-activation connectivity analysis for right hippocampus. (F) Functional characterization of right hippocampus. Functional characterization of significance levels was thresholded at p < 0.05, cluster-level FWE-corrected, cluster-forming threshold at voxel-level p < 0.001. Co-activation connectivity of significance levels was thresholded at p < 0.05, corrected for multiple comparisons using FDR.