Global Efficiency of Structural Networks Mediates Cognitive Control in Mild Cognitive Impairment

Background: Cognitive control has been linked to both the microstructure of individual tracts and the structure of whole-brain networks, but their relative contributions in health and disease remain unclear. Objective: To determine the contribution of both localized white matter tract damage and disruption of global network architecture to cognitive control, in older age and Mild Cognitive Impairment (MCI). Materials and Methods: Twenty-five patients with MCI and 20 age, sex, and intelligence-matched healthy volunteers were investigated with 3 Tesla structural magnetic resonance imaging (MRI). Cognitive control and episodic memory were evaluated with established tests. Structural network graphs were constructed from diffusion MRI-based whole-brain tractography. Their global measures were calculated using graph theory. Regression models utilized both global network metrics and microstructure of specific connections, known to be critical for each domain, to predict cognitive scores. Results: Global efficiency and the mean clustering coefficient of networks were reduced in MCI. Cognitive control was associated with global network topology. Episodic memory, in contrast, correlated with individual temporal tracts only. Relationships between cognitive control and network topology were attenuated by addition of single tract measures to regression models, consistent with a partial mediation effect. The mediation effect was stronger in MCI than healthy volunteers, explaining 23-36% of the effect of cingulum microstructure on cognitive control performance. Network clustering was a significant mediator in the relationship between tract microstructure and cognitive control in both groups. Conclusion: The status of critical connections and large-scale network topology are both important for maintenance of cognitive control in MCI. Mediation via large-scale networks is more important in patients with MCI than healthy volunteers. This effect is domain-specific, and true for cognitive control but not for episodic memory. Interventions to improve cognitive control will need to address both dysfunction of local circuitry and global network architecture to be maximally effective.