Abstract
Introduction: Mild cognitive impairment (MCI) is a heterogenous syndrome considered as a risk factor for developing dementia. Previous work examining morphological brain changes in MCI has identified a temporo-parietal atrophy pattern that suggests a common neuroanatomical denominator of cognitive impairment. Using functional connectivity analyses of structurally affected regions in MCI, we aimed to investigate and characterize functional networks formed by these regions that appear to be particularly vulnerable to disease-related disruptions.Methods: Areas of convergent atrophy in MCI were derived from a quantitative meta-analysis and encompassed left and right medial temporal (i.e., hippocampus, amygdala), as well as parietal regions (precuneus), which were defined as seed regions for connectivity analyses. Both task-based meta-analytical connectivity modeling (MACM) based on the BrainMap database and task-free resting-state functional MRI in a large cohort of older adults from the 1000BRAINS study were applied. We additionally assessed behavioral characteristics associated with the seed regions using BrainMap meta-data and investigated correlations of resting-state connectivity with age.Results: The left temporal seed showed stronger associations with a fronto-temporal network, whereas the right temporal atrophy cluster was more linked to cortico-striatal regions. In accordance with this, behavioral analysis indicated an emphasis of the left temporal seed on language generation, and the right temporal seed was associated with the domains of emotion and attention. Task-independent co-activation was more pronounced in the parietal seed, which demonstrated stronger connectivity with a frontoparietal network and associations with introspection and social cognition. Correlation analysis revealed both decreasing and increasing functional connectivity with higher age that may add to pathological processes but also indicates compensatory mechanisms of functional reorganization with increasing age.Conclusion: Our findings provide an important pathophysiological link between morphological changes and the clinical relevance of major structural damage in MCI. Multimodal analysis of functional networks related to areas of MCI-typical atrophy may help to explain cognitive decline and behavioral alterations not tractable by a mere anatomical interpretation and therefore contribute to prognostic evaluations.
Highlights
Mild cognitive impairment (MCI) is a heterogenous syndrome considered as a risk factor for developing dementia
Task-based functional connectivity of MCI-typical atrophy seeds was calculated via meta-analytic connectivity modeling [Meta-Analytic Connectivity Modeling (MACM); [20,21,22]] based on the BrainMap database [www.brainmap.org; [15, 23, 24]]
By examining the functional connectivity profile of co-activations reported across the entire brain, we aimed to identify functional networks connected with these atrophy regions and most likely to be disrupted in patients with MCI
Summary
Mild cognitive impairment (MCI) is a heterogenous syndrome considered as a risk factor for developing dementia. A comprehensive understanding of the clinical profile linked to such alterations should consider the complex interactions within neuronal circuits formed by or emanating from areas susceptible to disease pathology This is true given the notion that neurogenerative disorders represent diseases with distinct patterns of network disintegration [10, 11]. Neurodegenerative diseases have been described as “nexopathies” (Latin nectere, tie) referring to the spread of pathogenic protein abnormalities via large-scale brain networks and differential intrinsic network vulnerability [12] In this context, the regions of convergent volume loss in MCI identified by Nickl-Jockschat et al [8], which are parts of the default mode network (DMN), can be considered as network nodes vulnerable in MCI. A disruption of such circuits due to morphological changes will be detrimental to network functionality, which in turn may likely lead to clinical manifestations going beyond a merely anatomical interpretation of circumscribed atrophic regions
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