title: 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. Hum Brain Mapp 38:3249-3261, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Psychological and Brain Sciences, University of Delaware, Newark, Delaware, 19716.|Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, Massachusetts, 02130.|Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, 02130.
authors.forename: Jeffrey M
authors.identifier: 0000-0001-8348-7157
authors.initials: JM
authors.lastname: Spielberg
authors.affiliation: Department of Psychological and Brain Sciences, University of Delaware, Newark, Delaware, 19716.|National Center for Posttraumatic Stress Disorder, Behavioral Sciences Division, VA Boston Healthcare System, Boston, Massachusetts, 02130.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sadeh
authors.affiliation: Geriatric Research, Education & Clinical Center & Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, Massachusetts, 02130.|Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, 02215.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Leritz
authors.affiliation: Geriatric Research, Education & Clinical Center & Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, Massachusetts, 02130.|Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, 02215.
authors.forename: Regina E
authors.initials: RE
authors.lastname: McGlinchey
authors.affiliation: Geriatric Research, Education & Clinical Center & Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, Massachusetts, 02130.|Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, 02215.
authors.forename: William P
authors.initials: WP
authors.lastname: Milberg
authors.affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, 02130.|National Center for Posttraumatic Stress Disorder, Behavioral Sciences Division, VA Boston Healthcare System, Boston, Massachusetts, 02130.
authors.forename: Jasmeet P
authors.initials: JP
authors.lastname: Hayes
authors.affiliation: Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, Massachusetts, 02130.|Geriatric Research, Education & Clinical Center & Translational Research Center for TBI and Stress Disorders, VA Boston Healthcare System, Boston, Massachusetts, 02130.|Department of Radiology, Harvard Medical School, Boston, Massachusetts, 02129.
authors.forename: David H
authors.initials: DH
authors.lastname: Salat
mesh_terms: D000328:Adult; D000375:Aging; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D002784:Cholesterol / Q000097:blood*; D003072:Cognition Disorders / Q000097:blood* / Q000209:etiology / Q000473:pathology*; D004185:Disability Evaluation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009434:Neural Pathways / Q000503:physiopathology*; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D013313:Stress Disorders, Post-Traumatic / Q000097:blood / Q000473:pathology
chemical_list: D002784:Cholesterol; D010100:Oxygen
keywords: aging; caudate nucleus; cognition; graph theory; lipids; magnetic resonance imaging; risk factors; temporal lobe; veterans