White matter hyperintensities (WMH), which appear as regions of increased brightness on T2-weighted magnetic resonance scans of the human brain, are a major risk factor for stroke, dementia, and mortality. However, no large-scale investigations have looked at the relationship between WMH and circulating metabolites. For a study, researchers evaluated up to 9,290 people (50.7% of whom were female, with an average age of 61 years) from 15 populations of 8 community-based cohorts. The volume of the WMH was measured using T2-weighted or fluid-attenuated inversion recovery imaging or as hypointensities on T1-weighted images. Mass spectrometry and nuclear magnetic resonance spectroscopy were used to examine circulating metabolomic measures. Fitting linear regression models in the pooled sample and sex- and statin treatment–stratified subsamples were used to evaluate associations between WMH and metabolomic markers. The basic models were adjusted for age, gender, sex, and technical variables, and fully adjusted models were further adjusted for statin medication, hypertension, type 2 diabetes, smoking, BMI, and estimated glomerular filtration rate. The fixed-effect inverse variance–weighted technique was used to meta-analyze population-specific findings. Associations with (PFDR)<0.05 were deemed significant.
They detected 30 metabolomic markers linked with WMH (PFDR<0.05) in the meta-analysis of basic model findings, 7 of which remained significant in the fully adjusted models. The strongest significant correlation was with greater hydroxyphenylpyruvate levels in males (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) subsamples. In males, hydroxyphenylpyruvate explained 3–14% of the variation in WMH. WMH was also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins, as well as a larger diameter of low-density lipoprotein particles in men and the pooled sample, most likely due to higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. The only significant link in women was with greater levels of glucuronate (PFDR=0.047).
In a general population of middle-aged and older adults, 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. Some metabolomic measurements exhibit strong gender differences and account for a significant amount of WMH variation.
Reference:www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.056892
