Associations of Regional Brain Structural Differences With Aging, Modifiable Risk Factors for Dementia, and Cognitive Performance

Abstract

IMPORTANCE Identifying brain regions associated with risk factors for dementia could guide mechanistic understanding of risk factors associated with Alzheimer disease (AD). OBJECTIVES To characterize volume changes in brain regions associated with aging and modifiable risk factors for dementia (MRFD) and to test whether volume differences in these regions are associated with cognitive performance. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study used data from UK Biobank participants who underwent T1-weighted structural brain imaging from August 5, 2014, to October 14, 2016. A voxelwise linear model was applied to test for regional gray matter volume differences associated with aging and MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use). The potential clinical relevance of these associations was explored by comparing their neuroanatomical distributions with the regional brain atrophy found with AD. Mediation models for risk factors, brain volume differences, and cognitive measures were tested. The primary hypothesis was that common, overlapping regions would be found. Primary analysis was conducted on April 1, 2018. MAIN OUTCOMES AND MEASURES Gray matter regions that showed relative atrophy associated with AD, aging, and greater numbers of MRFD. RESULTS Among 8312 participants (mean [SD] age, 62.4 [7.4] years; 3959 [47.1%] men), aging and 4 major MRFD (ie, hypertension, diabetes, obesity, and frequent alcohol use) had independent negative associations with specific gray matter volumes. These regions overlapped neuroanatomically with those showing lower volumes in participants with AD, including the posterior cingulate cortex, the thalamus, the hippocampus, and the orbitofrontal cortex. Associations between these MRFD and spatial memory were mediated by differences in posterior cingulate cortex volume (β = 0.0014; SE = 0.0006; P = .02). CONCLUSIONS AND RELEVANCE This cross-sectional study identified differences in localized brain gray matter volume associated with aging and MRFD, suggesting regional vulnerabilities. These differences appeared relevant to cognitive performance even among people considered cognitively healthy.

Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders

“…Alternatively, our stringent multiple testing corrections to guard against false positives can potentially cause some true positives to be missed; a limitation of the approach. Analysis showed associations between higher brain age difference and type I and type II diabetes, a finding previously observed in other imaging studies 33 including analysis on UK biobank 10 and supported by previously recognised effects of diabetes on brain structure 34 , 35 . This study also revealed a direct association between brain age differences and vascular disease risk factors, particularly blood pressure.…”

“…Associations between brain age deviations using distinct approaches to ours but similar data from UK biobank also revealed associated between this phenotype and blood pressure adding internal validity to these results 10 . Although a relationship between hypertension and both cognitive decline and brain atrophy has already been established 35 , 36 , and prolonged hypertension is recognised to be associated with increased white matter pathology 37 , 38 the mechanisms of these associations are not well defined 39 . Physical fitness was associated with lower brain age difference highlighting the association of physical fitness not only to functional 40 , but also to structural changes of the brain.…”

Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort

“…The brain areas with associated iron deposition in p.C282Y homozygote men included the hippocampus and thalamus, two structures known to play important roles in memory function [ 23 ], and which are frequently affected in early Alzheimer’s disease [ 24 ], as well as in the putamen, where iron accumulation occurs with aging [ 25 ] and in geriatric depression [ 26 ]. Smaller putamen gray matter volumes have been reported in neurodegenerative disorders [ 27 ], including Alzheimer’s disease [ 28 ].…”

Alcohol consumption is associated with structural changes in various organ systems: A population-based study in UK Biobank

“…However, our observations may also reflect interactions between pathologies across organ systems. For example, alcohol is metabolized primarily in the liver, where it increases fatty acid synthesis(6) and leads to metabolic abnormalities that independently contribute to cardiovascular and brain pathologies(55-57).…”