Differences Changes in Cerebellar Functional Connectivity Between Mild Cognitive Impairment and Alzheimer's Disease: A Seed-Based Approach

Abstract

Background: Recent studies have discovered that functional connections are impaired among patients with Alzheimer's disease (AD), even at the preclinical stage. The cerebellum has been implicated as playing a role in cognitive processes. However, functional connectivity (FC) among cognitive sub-regions of the cerebellum in patients with AD and mild cognitive impairment (MCI) remains to be further elucidated. Objective: Our study aims to investigate the FC changes of the cerebellum among patients with AD and MCI, compared to healthy controls (HC). Additionally, we explored the role of cerebellum FC changes in the cognitive performance of all subjects. Materials: Resting-state functional magnetic resonance imaging (rs-fMRI) data from three different groups (28 AD patients, 26 MCI patients, and 30 HC) was collected. We defined cerebellar crus II and lobule IX as seed regions to assess the intragroup differences of cortico-cerebellar connectivity. Bias correlational analysis was performed to investigate the relationship between changes in FC and neuropsychological performance. Results: Compared to HC, AD patients had decreased FC within the caudate, limbic lobe, medial frontal gyrus (MFG), middle temporal gyrus, superior frontal gyrus, parietal lobe/precuneus, inferior temporal gyrus, and posterior cingulate gyrus. Interestingly, MCI patients demonstrated increased FC within inferior parietal lobe, and MFG, while they had decreased FC in the thalamus, inferior frontal gyrus, and superior frontal gyrus. Further analysis indicated that FC changes between the left crus II and the right thalamus, as well as between left lobule IX and the right parietal lobe, were both associated with cognitive decline in AD. Disrupted FC between left crus II and right thalamus, as well as between left lobule IX and right parietal lobe, was associated with attention deficit among subjects with MCI. Conclusion: These findings indicate that cortico-cerebellar FC in MCI and AD patients was significantly disrupted with different distributions, particularly in the default mode networks (DMN) and fronto-parietal networks (FPN) region. Increased activity within the fronto-parietal areas of MCI patients indicated a possible compensatory role for the cerebellum in cognitive impairment. Therefore, alterations in the cortico-cerebellar FC represent a novel approach for early diagnosis and a potential therapeutic target for early intervention.

Keywords: Azheimer's disease; cerebellum; functional connectivity; mild cognitive impairment; resting-state functional MRI.

Figure 1

The ROIs of the cerebellum. The image was transformed into the space of the SUIT atlas and was overlapped by the seeds. Red color represents the Crus II, and blue color represents the posterior lobule IX.

Figure 2

Differences of FC values in the cerebellum left crus II. (A) Brain regions showing significant differences in FC of the left cerebellum crus II based on analysis of variance (ANOVA) analysis between HC, AD, and aMCI, p < 0.05, the cluster size > 100 voxels). (B,C) Results of post-hoc two-sample T-tests in voxel-wise analysis (Bonferroni corrected, cluster size ≥ 30 voxels, p < 0.05). AD, Alzheimer's disease; aMCI, amnestic mild cognitive impairment; HC, healthy controls; LIM, limbic lobe; THA, Thalamus; MFG, Middle Frontal Gyrus; CAU, Caudate; CPL, cerebellum posterior lobe; L, left; R, right.

Figure 3

Differences of FC values in the right cerebellum Crus II. (A) Brain regions showing significant differences in FC of the right cerebellum Crus II based on analysis of variance (ANOVA) analysis between HC, AD, and aMCI patients, p < 0.05, the cluster size > 100 voxels). (B–D) The results of post-hoc two-sample T-tests in voxel-wise analysis (Bonferroni corrected, cluster size ≥ 30 voxels, p < 0.05). AD, Alzheimer's disease; aMCI, amnestic mild cognitive impairment; HC, healthy controls; SFG, superior frontal gyrus; IPL, inferior parietal lobe; MFG, Middle Frontal Gyrus; CAU, Caudate; LIM, limbic lobe; CPL, cerebellum posterior lobe; IFG, inferior frontal lobe; L, left; R, right.

Figure 4

Differences of FC values in the cerebellum left lobule IX. (A) Brain regions showing significant differences in FC of the cerebellum left lobule IX based on analysis of variance (ANOVA) analysis between HC, AD, and aMCI (p < 0.05; the cluster size > 100 voxels). (B,C) The results of post-hoc two-sample T-tests in voxel-wise analysis (Bonferroni corrected, cluster size ≥ 30 voxels, p < 0.05). AD, Alzheimer's disease; aMCI, amnestic mild cognitive impairment; HC, healthy controls; SPL, superior parietal lobe; PL, parietal lobe; CAL, cerebellum Anterior lobe; L, left; R, right.

Figure 5

Differences of FC values in the cerebellum right lobule IX. (A) Brain regions showing significant differences in FC of the right lobule IX based on analysis of variance (ANOVA) analysis between HC, AD, and aMCI; p < 0.05, the cluster size > 100 voxels. (B–D) The results of post-hoc two-sample T-tests in voxel-wise analysis (Bonferroni corrected, cluster size ≥ 30 voxels, p < 0.05). AD, Alzheimer's disease; aMCI, amnestic mild cognitive impairment; HC, healthy controls; MFG, Middle Frontal Gyrus; IPL, inferior parietal lobe; LIM, limbic lobe; PCG, posterior cingulate gyrus; SFG, superior frontal gyrus; CAL, cerebellum Anterior lobe; CPL, cerebellum posterior lobe; THA, Thalamus; ITG, inferior temporal gyrus; CAU, Caudate; L, left; R, right.

Figure 6

Correlation between the functional connectivity (FC) and cognitive function scores in the AD (blue point) and aMCI (green point) patients. (A–F) Significant correlation between FC changes and cognitive function scales include MOCA, STT-A, DST, VFT in cerebellum crus II and lobule IX (Bonferroni corrected, p < 0.05). Age, gender, and years of education were used to control variables of the results. AD, Alzheimer's disease; aMCI, amnesic mild cognitive impairment; MOCA, Montreal Cognitive Assessment; DST, Digit Span Test; VTF, Verbal Fluency Test; TMT, Trail Making Test; R, right; L, left.