Higher serum cholesterol is associated with intensified age‐related neural network decoupling and cognitive decline in early‐ to mid‐life

Abstract

Mounting evidence indicates that serum cholesterol and other risk factors for cardiovascular disease intensify normative trajectories of age-related cognitive decline. However, the neural mechanisms by which this occurs remain largely unknown. To understand the impact of cholesterol on brain networks, we applied graph theory to resting-state fMRI in a large sample of early- to mid-life Veterans (N = 206, Meanage = 32). A network emerged (centered on the banks of the superior temporal sulcus) that evidenced age-related decoupling (i.e., decreased network connectivity with age), but only in participants with clinically-elevated total cholesterol (≥180 mg/dL). Crucially, decoupling in this network corresponded to greater day-to-day disability and mediated age-related declines in psychomotor speed. Finally, examination of network organization revealed a pattern of age-related dedifferentiation for the banks of the superior temporal sulcus, again present only with higher cholesterol. More specifically, age was related to decreasing within-module communication (indexed by Within-Module Degree Z-Score) and increasing between-module communication (indexed by Participation Coefficient), but only in participants with clinically-elevated cholesterol. Follow-up analyses indicated that all findings were driven by low-density lipoprotein (LDL) levels, rather than high-density lipoprotein (HDL) or triglycerides, which is interesting as LDL levels have been linked to increased risk for cardiovascular disease, whereas HDL levels appear inversely related to such disease. These findings provide novel insight into the deleterious effects of cholesterol on brain health and suggest that cholesterol accelerates the impact of age on neural trajectories by disrupting connectivity in circuits implicated in integrative processes and behavioral control.

Clinically significant cognitive dysfunction in OEF/OIF/OND veterans: Prevalence and clinical associations.

“…However, it is possible that the structural MRI scans used in this study were not ideal for detecting the changes in brain structure or anatomy related to CD. Diffusion imaging or functional MRI may be more sensitive to differences in this population (Poole et al, 2016; Spielberg et al, 2017). Future investigations using a more comprehensive battery of neuroimaging measures would be useful to determine whether there are neural differences between groups.…”

Large-Scale Internetwork Functional Connectivity Mediates the Relationship between Serum Triglyceride and Working Memory in Young Adulthood

“…In a resting-state fMRI study of nondemented elderly, higher serum TC was shown to associate with lower functional connectivity in the salience network yet stronger connectivity in the default mode network [ 16 ]. Another resting-state fMRI based on graph theory suggested that higher serum LDL-C level was associated with intensified age-related neural network decoupling (i.e., decreased network connectivity with age) [ 17 ]. By employing structural MRI, Ward et al observed an association between lower serum HDL-C and reduced gray matter volume in the temporal, occipital, and parahippocampal regions in a sample of middle-aged and elderly people [ 12 ].…”

“…There have been several neuroimaging studies attempting to clarify the associations between serum lipids and the brain in both normal and disease-affected populations. As a consequence, previous findings consistently suggest a negative effect of serum TC, TG, and LDL-C yet a protective effect of HDL-C on brain structure and function, by using structural magnetic resonance imaging (MRI) to evaluate gray matter morphology [ 5 , 12 – 14 ] and using functional MRI (fMRI) to measure task-induced brain activation [ 15 ] and resting-state functional connectivity [ 4 , 16 , 17 ]. Nevertheless, whether and how differences in serum lipid parameters relate to variations in neuroimaging phenotypes in healthy young adults is still an open question.…”

Linking genes, circuits, and behavior: network connectivity as a novel endophenotype of externalizing

“…All analyses were adjusted for age, sex, the first two ancestry principal components, deployment-related blast exposure (Fortier et al ., 2014), handedness, current employment, and total cholesterol. Covariates were selected based on demonstrated associations with neural connectivity/integrity, genetic effects, and/or externalizing phenotypes in previous research (Price et al ., 2006; Han et al ., 2014; Spielberg et al ., 2017). Given high rates of trauma exposure, posttraumatic stress disorder, and mild TBI in this sample, we also examined whether these variables and other comorbidities altered study findings and found that they did not (see online Supplementary Results for details).…”