Circulating Metabolome and White Matter Hyperintensities in Women and Men

Abstract

Background: White matter hyperintensities (WMH) are identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness; WMH are a major risk factor of stroke, dementia, and death. Currently, there are no large-scale studies testing associations between WMH and circulating metabolites. Methods: We studied up to 9,290 individuals (50.7% females, 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 additionally 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 ( p FDR )<0.05 were considered significant. Results: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH ( p FDR <0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in males ( p FDR.full.adj =1.40×10 -7 ) and in both the pooled sample ( p FDR.full.adj =1.66×10 -4 ) and statin-nontreated ( p FDR.full.adj =1.65×10 -6 ) subsample. In males, HPP explained 3-14% of variance in WMH. In males 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 females, the only significant association was with higher level of glucuronate ( p FDR =0.047). Conclusions: Circulating metabolomic measures, including multiple lipid measures (e.g., lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and non-lipid metabolites (e.g., hydroxyphenylpyruvate, glucuronate) associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain sizable proportion of WMH variance.

The global burden of cerebral small vessel disease in low- and middle-income countries: A systematic review and meta-analysis

“…62 While this may reflect recruitment bias seen in many hospital-based stroke treatment trials that include neuroimaging for cSVD, it may also imply that males develop higher cSVD severity, especially in stroke presentations which may, in turn, reflect male: female ratio differences in metabolomic. 63 Conversely, the male: female ratio did not predict cSVD prevalence in this meta-analysis, possibly due to the diluting effect of community-based studies in which cSVD prevalences are low.…”

Investigating associations between blood metabolites, later life brain imaging measures, and genetic risk for Alzheimer’s disease

“…Our findings were observed for sphingomyelins in particular, a subclass that are especially abundant in the CNS, where they form pivotal components of neuronal membranes and play key roles in signal transduction (49). Given their biological role, it is unsurprising that sphingolipids have been previously linked to brain health and pathology (50,51). Here, we report associations between a module enriched in sphingolipids and hippocampal volume, as well as several sphingomyelin hub metabolites and whole-brain volume.…”

What Turns the White Matter White? Metabolomic Clues to the Origin of Age-Related Cerebral White Matter Hyperintensities

“…In the study by Sliz et al, individual vascular risk factors such as hypertension explained 1% or less of the variance of WMH in each of their cohorts. 2 Analysis of other cohorts has also found that conventional vascular risk factors explain 2% or less of the variation in WMH. 5 In contrast, conventional vascular risk factors and age account for more than half of the variance in carotid atherosclerotic plaque.…”

“…7 Using these methods, they were able to test 2217 metabolites and lipoproteins in serum from participants in 8 community-based cohort studies. 2 Accounting for multiple hypothesis testing using the false discovery rate method, they found associations between WMH and hydroxyphenylpyruvate (an amino acid metabolite), glucose metabolism products, lipids, cell membrane components (lysophosphatidylcholines), and myelin components (hydroxysphingomyelins). It is interesting, but of unclear significance, that they also found evidence of modification by sex, with most associations significant in men only.…”