Association of Age and Structural Brain Changes With Functional Connectivity and Executive Function in a Middle-Aged to Older Population-Based Cohort.

Maximilian Schulz,Eckhard Schlemm,Marvin Petersen,Caroline Malherbe,Uta Hanning,Götz Thomalla,Bastian Cheng,Benedikt M Frey,Raphael Twerenbold,Jens Fiehler,Simone Kühn,Jürgen Gallinat,Carola Mayer,Christian Gerloff

doi:10.3389/fnagi.2022.782738

Abstract

Aging is accompanied by structural brain changes that are thought to underlie cognitive decline and dementia. Yet little is known regarding the association between increasing age, structural brain damage, and alterations of functional brain connectivity. The aim of this study was to evaluate whether cortical thickness and white matter damage as markers of age-related structural brain changes are associated with alterations in functional connectivity in non-demented healthy middle-aged to older adults. Therefore, we reconstructed functional connectomes from resting-state functional magnetic resonance imaging (MRI) (rsfMRI) data of 976 subjects from the Hamburg City Health Study, a prospective population-based study including participants aged 45–74 years from the metropolitan region Hamburg, Germany. We performed multiple linear regressions to examine the association of age, cortical thickness, and white matter damage quantified by the peak width of skeletonized mean diffusivity (PSMD) from diffusion tensor imaging on whole-brain network connectivity and four predefined resting state networks (default mode, dorsal, salience, and control network). In a second step, we extracted subnetworks with age-related decreased functional connectivity from these networks and conducted a mediation analysis to test whether the effect of age on these networks is mediated by decreased cortical thickness or PSMD. We observed an independent association of higher age with decreased functional connectivity, while there was no significant association of functional connectivity with cortical thickness or PSMD. Mediation analysis identified cortical thickness as a partial mediator between age and default subnetwork connectivity and functional connectivity within the default subnetwork as a partial mediator between age and executive cognitive function. These results indicate that, on a global scale, functional connectivity is not determined by structural damage in healthy middle-aged to older adults. There is a weak association of higher age with decreased functional connectivity which, for specific subnetworks, appears to be mediated by cortical thickness.

Highlights

Higher age is accompanied by structural brain alterations, which are thought to give rise to functional abnormalities and decline in cognitive function, even in individuals free of neurodegenerative disease
We studied the influence of age, microstructural white matter damage, and cortical thinning on functional connectivity (FC) and executive cognitive function in a healthy population at increased cardiovascular risk
We identified a significant association of age with all the structural and functional imaging parameters and cognition, the association between age and FC was weak

Summary

Introduction

Higher age is accompanied by structural brain alterations, which are thought to give rise to functional abnormalities and decline in cognitive function, even in individuals free of neurodegenerative disease. Modern brain magnetic resonance imaging (MRI) studies provide an opportunity to probe in vivo for changes in structural and functional imaging biomarkers during the aging process. Researchers observed many neuroimaging measures of brain structure and function that indicate deterioration during adult aging (Hedden and Gabrieli, 2004; Walhovd et al, 2011; Grady, 2012; Chen et al, 2016) with cortical thickness, white matter hyperintensity (WMH) load, and functional connectivity (FC) being the most prominent parameters. White matter damage visible by hyperintensities (WMH) on T2-weighted MR images represents microvascular ischemic and demyelinating alterations (Chui, 2006; Launer et al, 2006). Primary contributors to the development of microvascular damage include arteriolosclerosis as well as cardiovascular risk factors such as arterial hypertension, diabetes, and smoking (Stephan et al, 2009; Power et al, 2015; Frey et al, 2019)

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