Abnormal global functional network connectivity and its relationship to medial temporal atrophy in patients with amnestic mild cognitive impairment

Abstract

Background: Amnestic mild cognitive impairment (aMCI), which is recently considered as a high risk status for developing Alzheimer's disease (AD), manifests with gray matter atrophy and increased focal functional activity in the medial temporal lobe (MTL). However, the abnormalities of whole-brain functional network connectivity in aMCI and its relationship to medial temporal atrophy (MTA) remain unknown.

Methods: In this study, thirty-six aMCI patients and thirty-five healthy controls (HCs) were recruited. Neuropsychological assessments and MTA visual rating scaling were carried out on all participants. Furthermore, whole brain functional network was constructed at voxel level, and functional connectivity strength (FCS) was computed as the sum of the connections for each node to capture its global integrity. General linear model was used to analyze the FCS values differences between aMCI and HCs. Then, the regions showing significant FCS differences were adopted as the imaging markers for discriminative analysis. Finally, the relationship between FCS values and clinical cognitive scores was correlated in patients with aMCI.

Results: Comparing to HCs, aMCI exhibited significant atrophy in the MTL, while higher FCS values within the bilateral MTL regions and orbitofrontal cortices. Notably, the right hippocampus had the highest classification power, with the area under receiver operating characteristics (ROC) curve (AUC) of 0.790 (confidence interval: 0.678, 0.901). Moreover, FCS values of the right hippocampus and the left temporal pole were positively correlated with the cognitive performance in aMCI.

Conclusion: This study demonstrated significantly structural atrophy and raised global functional integrity in the MTL, suggesting simultaneous disruption and compensation in prodromal AD. Increased intrinsic functional connectivity in the MTL may have the potential to discriminate subjects with tendency to develop AD.

Fig 1. The FCS in aMCI and HCs and the group differences.

(A) and (B) These two pictures showed the mean FCS both in aMCI and HCs. The color bar represents the FCS value for each group and the warm color means higher FCS value. (C) This picture indicated the group differences between aMCI patients and HCs on FCS value. The color bar at the bottom represents T value (p < 0.05, Cluster > 309 voxels). FCS, functional connectivity strength; aMCI, amnestic mild cognitive impairments; HC, healthy controls.

Fig 2. FCS-based classification analysis.

The ROC of FCS in the right hippocampus (A), the left hippocampus (B), and the bilateral cuneus (C) in distinguishing individuals with aMCI from HCs. FCS, functional connectivity strength.

Fig 3. Correlation between FCS and clinical scores in aMCI patients.

(A) This picture showed marginally positive correlation between FCS value of right hippocampus and AVLT-D (R = 0. 439, P = 0.007, corrected-P = 0.042); (B) This picture showed the positive correlation between FCS value of left TPOmid and AVLT-R (R = 0.547, P = 0.001, corrected-P = 0.006); (C) This picture showed the marginally positive correlation between FCS value of right hippocampus and AVLT-R (R = 0.405, P = 0.014, corrected-P = 0.084). FCS, functional connectivity strength; aMCI, amnestic mild cognitive impairments; HIP, hippocampus; TPOmid, temporal pole (middle), AVLT-D, auditory verbal learning test-delayed recall; AVLT-R, auditory verbal learning test-recognition.

Fig 4. Validation of FCS-based classification analysis for different FCS thresholds.

The ROC of FCS in the right hippocampus (red), the left hippocampus (blue), and the bilateral cuneus (green) in distinguishing individuals with aMCI from HCs under FCS threshold of 0.1 (A) and 0.3 (B). FCS, functional connectivity strength.