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APOE Genotype Effects on Intrinsic Brain Network Connectivity in Patients with Amnestic Mild Cognitive Impairment.

ABSTRACT: Whether and how the apolipoprotein E (APOE) ?4 genotype specifically modulates brain network connectivity in patients with amnestic mild cognitive impairment (aMCI) remain largely unknown. Here, we employed resting-state ('task-free') functional MRI and network centrality approaches to investigate local (degree centrality, DC) and global (eigenvector centrality, EC) functional integrity in the whole-brain connectome in 156 older adults, including 66 aMCI patients (27 ?4-carriers and 39 non-carriers) and 90 healthy controls (45 ?4-carriers and 45 non-carriers). We observed diagnosis-by-genotype interactions on DC in the left superior/middle frontal gyrus, right middle temporal gyrus and cerebellum, with higher values in the ?4-carriers than non-carriers in the aMCI group. We further observed diagnosis-by-genotype interactions on EC, with higher values in the right middle temporal gyrus but lower values in the medial parts of default-mode network in the ?4-carriers than non-carriers in the aMCI group. Notably, these genotype differences in DC or EC were absent in the control group. Finally, the network connectivity DC values were negatively correlated with cognitive performance in the aMCI ?4-carriers. Our findings suggest that the APOE genotype selectively modulates the functional integration of brain networks in patients with aMCI, thus providing important insight into the gene-connectome interaction in this disease.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5428452 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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APOE Genotype Effects on Intrinsic Brain Network Connectivity in Patients with Amnestic Mild Cognitive Impairment.

Wang Zan Z Dai Zhengjia Z Shu Hao H Liao Xuhong X Yue Chunxian C Liu Duan D Guo Qihao Q He Yong Y Zhang Zhijun Z

Scientific reports 20170324 1

Whether and how the apolipoprotein E (APOE) ε4 genotype specifically modulates brain network connectivity in patients with amnestic mild cognitive impairment (aMCI) remain largely unknown. Here, we employed resting-state ('task-free') functional MRI and network centrality approaches to investigate local (degree centrality, DC) and global (eigenvector centrality, EC) functional integrity in the whole-brain connectome in 156 older adults, including 66 aMCI patients (27 ε4-carriers and 39 non-carri ...[more]

PMID: 28341847

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Project description:BackgroundResting-state functional magnetic resonance imaging studies using a regional homogeneity (ReHo) method have reported that amnestic mild cognitive impairment (aMCI) was associated with abnormalities in local functional connectivity. However, their results were not conclusive.MethodsSeed-based d Mapping was used to conduct a coordinate-based meta-analysis to identify consistent ReHo alterations in aMCI.ResultsWe identified 10 studies with 11 datasets suitable for inclusion, including 378 patients with aMCI and 435 healthy controls. This meta-analysis identified significant ReHo alterations in patients with aMCI relative to healthy controls, mainly within the default mode network (DMN) (bilateral posterior cingulate cortex [PCC], right angular gyrus, bilateral middle temporal gyri, and left parahippocampal gyrus/hippocampus), executive control network (right superior parietal lobule and dorsolateral prefrontal cortex), visual network (right lingual gyrus and left middle occipital gyrus), and sensorimotor network (right paracentral lobule/supplementary motor area, right postcentral gyrus and left posterior insula). Significant heterogeneity of ReHo alterations in the bilateral PCC, left parahippocampal gyrus/hippocampus, and right superior parietal lobule/angular gyrus was observed. Exploratory meta-regression analyses indicated that general cognitive function, gender distribution, age, and education level partially contributed to this heterogeneity.ConclusionsThis study provides provisional evidence that aMCI is associated with abnormal ReHo within the DMN, executive control network, visual network, and sensorimotor network. These local functional connectivity alterations suggest coexistence of functional deficits and compensation in these networks. These findings contribute to the modeling of brain functional connectomes and to a better understanding of the neural substrates of aMCI. Confounding factors merit much attention and warrant future investigations.

Project description:Patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.We examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.We demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.We demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

Project description:Background: Subjective cognitive decline and amnestic mild cognitive impairment (aMCI) were widely thought to be preclinical AD spectrum disorders, characterized by aberrant functional connectivity (FC) within the triple networks of the default mode network (DMN), the salience network (SN), and the executive control network (ECN). Dynamic FC (DFC) analysis can capture temporal fluctuations in brain FC during the scan, which static FC analysis cannot. The purpose of the current study was to explore the changes in dynamic FC within the triple networks of the preclinical AD spectrum and further reveal their potential diagnostic value in diagnosing preclinical AD spectrum disorders. Methods: We collected resting-state functional magnetic resonance imaging data from 44 patients with subjective cognitive decline (SCD), 49 with aMCI, and 58 healthy controls (HCs). DFC analysis based on the sliding time-window correlation method was used to analyze DFC variability within the triple networks in the three groups. Then, correlation analysis was conducted to reveal the relationship between altered DFC variability within the triple networks and a decline in cognitive function. Furthermore, logistic regression analysis was used to assess the diagnostic accuracy of altered DFC variability within the triple networks in patients with SCD and aMCI. Results: Compared with the HC group, the groups with SCD and aMCI both showed altered DFC variability within the triple networks. DFC variability in the right middle temporal gyrus and left inferior frontal gyrus (IFG) within the ECN were significantly different between patients with SCD and aMCI. Moreover, the altered DFC variability in the left IFG within the ECN was obviously associated with a decline in episodic memory and executive function. The logistic regression analysis showed that multivariable analysis had high sensitivity and specificity for diagnosing SCD and aMCI. Conclusions: Subjective cognitive decline and aMCI showed varying degrees of change in DFC variability within the triple networks and altered DFC variability within the ECN involved episodic memory and executive function. More importantly, altered DFC variability and the triple-network model proved to be important biomarkers for diagnosing and identifying patients with preclinical AD spectrum disorders.

Project description:Background: The "primacy effect," i.e., increased memory recall for the first items of a series compared to the following items, is reduced in amnestic mild cognitive impairment (aMCI). Memory task-fMRI studies demonstrated that primacy recall is associated with higher activation of the hippocampus and temporo-parietal and frontal cortical regions in healthy subjects. Functional magnetic resonance imaging (fMRI) at resting state revealed that hippocampus functional connectivity (FC) with neocortical brain areas, including regions of the default mode network (DMN), is altered in aMCI. The present study aimed to investigate whether resting state fMRI FC between the hippocampus and cortical brain regions, especially the DMN, is associated with primacy recall performance in aMCI. Methods: A number of 87 aMCI patients underwent resting state fMRI and verbal episodic memory assessment. FC between the left or right hippocampus, respectively, and all other voxels in gray matter was mapped voxel-wise and used in whole-brain regression analyses, testing whether FC values predicted delayed primacy recall score. The delayed primacy score was defined as the number of the first four words recalled on the California Verbal Learning Test. Additionally, a partial least squares (PLS) analysis was performed, using DMN regions as seeds to identify the association of their functional interactions with delayed primacy recall. Results: Voxel-based analyses indicated that delayed primacy recall was mainly (positively) associated with higher FC between the left and right hippocampus. Additionally, significant associations were found for higher FC between the left hippocampus and bilateral temporal cortex, frontal cortical regions, and for higher FC between the right hippocampus and right temporal cortex, right frontal cortical regions, left medial frontal cortex and right amygdala (p < 0.01, uncorr.). PLS analysis revealed positive associations of delayed primacy recall with FC between regions of the DMN, including the left and right hippocampus, as well as middle cingulate cortex and thalamus (p < 0.04). In conclusion, in the light of decreased hippocampus function in aMCI, inter-hemispheric hippocampus FC and hippocampal FC with brain regions predominantly included in the DMN may contribute to residual primacy recall in aMCI.

Dataset Information

APOE Genotype Effects on Intrinsic Brain Network Connectivity in Patients with Amnestic Mild Cognitive Impairment.

Publications

APOE Genotype Effects on Intrinsic Brain Network Connectivity in Patients with Amnestic Mild Cognitive Impairment.

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