Circulating Metabolome and White Matter Hyperintensities in Women and Men.

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

Progression of White Matter Disease and Cortical Thinning Are Not Related in Older Community-Dwelling Subjects.

BACKGROUND AND PURPOSE: We assessed cross-sectional and longitudinal relationships between whole brain white matter hyperintensity (WMH) volume and regional cortical thickness. METHODS: We measured WMH volume and regional cortical thickness on magnetic resonance imaging at ≈73 and ≈76 years in 351 community-dwelling subjects from the Lothian Birth Cohort 1936. We used multiple linear regression to calculate cross-sectional and longitudinal associations between regional cortical thickness and WMH volume controlling for age, sex, Mini Mental State Examination, education, intelligence quotient at age 11, and vascular risk factors. RESULTS: We found cross-sectional associations between WMH volume and cortical thickness within and surrounding the Sylvian fissure at 73 and 76 years (rho=-0.276, Q=0.004). However, we found no significant longitudinal associations between (1) baseline WMH volume and change in cortical thickness; (2) baseline cortical thickness and change in WMH volume; or (3) change in WMH volume and change in cortical thickness. CONCLUSIONS: Our results show that WMH volume and cortical thinning both worsen with age and are associated cross-sectionally within and surrounding the Sylvian fissure. However, changes in WMH volume and cortical thinning from 73 to 76 years are not associated longitudinally in these relatively healthy older subjects. The underlying cause(s) of WMH growth and cortical thinning have yet to be fully determined.

Life-course neighbourhood deprivation and brain structure in older adults: The Lothian Birth Cohort 1936.

Neighbourhood disadvantage may be associated with brain health but the importance at different stages of the life course is poorly understood. Utilizing the Lothian Birth Cohort 1936, we explored the relationship between residential neighbourhood deprivation from birth to late adulthood, and global and regional neuroimaging measures at age 73. We found that residing in disadvantaged neighbourhoods in mid- to late adulthood was associated with smaller total brain (ß=-0.06; SE=0.02; n=390) and grey matter volume (ß=-0.11; SE=0.03; n=390), thinner cortex (ß=-0.15; SE=0.06; n=379), and lower general white matter fractional anisotropy (ß=-0.19; SE=0.06; n=388). Regional analysis identified affected focal cortical areas and specific white matter tracts. Among individuals belonging to lower occupational social classes, the brain-neighbourhood associations were stronger, with the impact of neighbourhood deprivation accumulating across the life course. Our findings suggest that living in deprived neighbourhoods is associated with adverse brain morphologies, with occupational social class adding to the vulnerability.

Aging-Sensitive Networks Within the Human Structural Connectome Are Implicated in Late-Life Cognitive Declines.

BACKGROUND: Aging-related cognitive decline is a primary risk factor for Alzheimer's disease and related dementias. More precise identification of the neurobiological bases of cognitive decline in aging populations may provide critical insights into the precursors of late-life dementias. METHODS: Using structural and diffusion brain magnetic resonance imaging data from the UK Biobank (n = 8185; age range, 45-78 years), we examined aging of regional gray matter volumes (nodes) and white matter structural connectivity (edges) within 9 well-characterized networks of interest in the human brain connectome. In the independent Lothian Birth Cohort 1936 (n = 534; all 73 years of age), we tested whether aging-sensitive connectome elements are enriched for key domains of cognitive function before and after controlling for early-life cognitive ability. RESULTS: In the UK Biobank, age differences in individual connectome elements corresponded closely with principal component loadings reflecting connectome-wide integrity (|rnodes| = .420; |redges| = .583), suggesting that connectome aging occurs on broad dimensions of variation in brain architecture. In the Lothian Birth Cohort 1936, composite indices of node integrity were predictive of all domains of cognitive function, whereas composite indices of edge integrity were associated specifically with processing speed. Elements within the central executive network were disproportionately predictive of late-life cognitive function relative to the network's small size. Associations with processing speed and visuospatial ability remained after controlling for childhood cognitive ability. CONCLUSIONS: These results implicate global dimensions of variation in the human structural connectome in aging-related cognitive decline. The central executive network may demarcate a constellation of elements that are centrally important to age-related cognitive impairments.

Dietary patterns, cognitive function, and structural neuroimaging measures of brain aging.

OBJECTIVE: To examine the cross-sectional associations between dietary patterns and cognitive and neuroimaging indices of brain health concurrently in the same sample of healthy older adults. METHODS: Dietary patterns were derived from a 130-item food frequency questionnaire for 511 individuals in the Lothian Birth Cohort 1936 (mean age 79.3 ± 0.6 years). Composite scores for global cognitive function, visuospatial ability, processing speed, memory, and verbal ability were assessed. Brain volumes and white matter microstructure were assessed in participants (n = 358) who also underwent structural magnetic resonance imaging. RESULTS: A Mediterranean-style dietary pattern and a processed dietary pattern were identified using principal component analysis of food frequency questionnaire items. In fully-adjusted linear regression models, adherence to the Mediterranean-style pattern was associated with better verbal ability (ß = 0.121, P = 0.002). Associations with global cognitive function (ß = 0.094, P = 0.043), visuospatial ability (ß = 0.113, P = 0.019), and memory (ß = 0.105, P = 0.029) did not survive correction for multiple comparisons. Associations between the processed pattern and lower cognitive scores were attenuated by around 50% following adjustment for prior (childhood) cognitive ability; only an association with verbal ability remained (ß = -0.130, P = 0.001). Neither dietary pattern was associated with brain volumes or white matter microstructure. Specific Mediterranean diet features-green leafy vegetables and a low intake of red meat-were associated with better cognitive functioning. CONCLUSIONS: These observational findings suggest that adherence to a Mediterranean-style diet is associated with better cognitive functioning, but not better brain structural integrity, in older adults.