Identifying the Alteration Patterns of Brain Functional Connectivity in Progressive Mild Cognitive Impairment Patients: A Longitudinal Whole-Brain Voxel-Wise Degree Analysis

Yanjia Deng, Kai Liu, Lin Shi, Yi Lei, Peipeng Liang, Kuncheng Li, Winnie C W Chu, Defeng Wang, Alzheimer's Disease Neuroimaging Initiative, Yanjia Deng, Kai Liu, Lin Shi, Yi Lei, Peipeng Liang, Kuncheng Li, Winnie C W Chu, Defeng Wang, Alzheimer's Disease Neuroimaging Initiative

Abstract

Patients with mild cognitive impairment (MCI) are at high risk for developing Alzheimer's disease (AD), while some of them may remain stable over decades. The underlying mechanism is still not fully understood. In this study, we aimed to explore the connectivity differences between progressive MCI (PMCI) and stable MCI (SMCI) individuals on a whole-brain scale and on a voxel-wise basis, and we also aimed to reveal the differential dynamic alteration patterns between these two disease subtypes. The resting-state functional magnetic resonance images of PMCI and SMCI patients at baseline and year-one were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset, and the progression was determined based on a 3-year follow-up. A whole-brain voxel-wise degree map that was calculated based on graph-theory was constructed for each subject, and then the cross-sectional and longitudinal analyses on the degree maps were performed between PMCI and SMCI patients. In longitudinal analyses, compared with SMCI group, PMCI group showed decreased long-range degree in the left middle occipital/supramarginal gyrus, while the short-range degree was increased in the left supplementary motor area and middle frontal gyrus and decreased in the right middle temporal pole. A significant longitudinal alteration of decreased short-range degree in the right middle occipital was found in PMCI group. Taken together with previous evidence, our current findings may suggest that PMCI, compared with SMCI, might be a "severe" presentation of disease along the AD continuum, and the rapidly reduced degree in the right middle occipital gyrus may have indicative value for the disease progression. Moreover, the cross-sectional comparison results and corresponding receiver-operator characteristic-curves analyses may indicate that the baseline degree difference is not a good predictor of disease progression in MCI patients. Overall, these findings may provide objective evidence and an indicator to characterize the progression-related brain connectivity changes in MCI patients.

Keywords: Alzheimer’s disease; connectome; functional connectivity; mild cognitive impairment; resting-state functional magnetic resonance imaging.

Figures

FIGURE 1
FIGURE 1
The mean long-range degree maps of progressive mild cognitive impairment (PMCI) group and stable MCI (SMCI) group and the longitudinal analyses results across the correlation threshold range of 0.2–0.4. In row (A,B), the mean long-range degree maps of SMCI and PMCI groups at baseline and year-one are shown, respectively. In row (C), the green-blue indicates brain regions with significantly decreased long-range degree in PMCI group compared with SMCI group (controlling for the effect of time). In row (D), the yellow–red indicates brain regions with a significant longitudinal increase of long-range degree in the PMCI group in 1-year duration compared with SMCI group (Statistical level: p < 0.01 with a minimal cluster size of 54 voxels, which yields an Alphasim correction threshold of p < 0.05).
FIGURE 2
FIGURE 2
The mean short-range degree maps of progressive mild cognitive impairment (PMCI) group and stable MCI (SMCI) group and the longitudinal analyses results across the correlation threshold range of 0.2–0.4. In row (A,B), the mean short-range degree maps of SMCI and PMCI groups at baseline and year-one are shown, respectively. In row (C), the green–blue/red–yellow indicates brain regions with significantly decreased/increased short-range degree in the PMCI group compared with the SMCI group (controlling for the effect of time). In row (D), the green–blue/red–yellow indicates the brain regions with a significant longitudinal decrease/increase of short-range degree in the PMCI group in 1-year duration compared with SMCI group (Statistical level: p < 0.01 with a minimal cluster size of 54 voxels, which yields an Alphasim correction threshold of p < 0.05).
FIGURE 3
FIGURE 3
The mean degree maps of the PMCI group and stable MCI (SMCI) group and baseline cross-sectional analyses results across the correlation threshold range of 0.2–0.4. The upper panel shows the mean long-range degree maps of SMCI (row A) and PMCI (row B) groups and the between-group comparison results (row C). In row (C), the green–blue/red–yellow indicates the brain regions with significantly decreased/increased long-range degree in the PMCI group compared with the SMCI group at baseline. The lower panel shows the mean short-range degree maps of SMCI (row D) and PMCI groups (row E) and the between-group comparison results (row F). In row (F), the red–yellow indicates the brain regions with significantly increased short-range degree in the PMCI group compared with the SMCI group at baseline. (Statistical level: p < 0.01 with a minimal cluster size of 48 voxels, which yields an Alphasim correction threshold of p < 0.05).
FIGURE 4
FIGURE 4
The Receiver-operator characteristic-curves (ROCs) based on the degree value of brain regions with significant cross-sectional difference between PMCI and stable MCI (SMCI) groups at baseline. (A) The ROC of the long-range degree in the right middle temporal gyrus; (B) The ROC of the short-range degree in the left cerebellum.

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