Circulating Metabolome and White Matter Hyperintensities in Women and Men, 2022, Sliz et al.

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Circulating Metabolome and White Matter Hyperintensities in Women and Men
Eeva Sliz; Jean Shin; Shahzad Ahmad; Dylan M. Williams; Stefan Frenzel; Friederike Gauß; Sarah E. Harris; Ann-Kristin Henning; Maria Valdes Hernandez; Yi-Han Hu; Beatriz Jiménez; Muralidharan Sargurupremraj; Carole Sudre; Ruiqi Wang; Katharina Wittfeld; Qiong Yang; Joanna M. Wardlaw; Henry Völzke; Meike W. Vernooij; Jonathan M. Schott; Marcus Richards; Petroula Proitsi; Matthias Nauck; Matthew R. Lewis; Lenore Launer; Norbert Hosten; Hans J. Grabe; Mohsen Ghanbari; Ian J. Deary; Simon R. Cox; Nishi Chaturvedi; Josephine Barnes; Jerome I. Rotter; Stephanie Debette; M. Arfan Ikram; Myriam Fornage; Tomas Paus; Sudha Seshadri; Zdenka Pausova; for the NeuroCHARGE Working Group

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.

What Is New?

• This is the first large-scale study to identify circulating metabolomic measures associated with white matter hyperintensities (WMH) volume, which is the most common brain imaging marker of small vessel disease and a major risk factor for incident stroke, dementia, and all-cause mortality.

• The metabolomic profile of WMH volume appears largely sex specific.

• The most significant metabolite, hydroxyphenylpyruvate, explains up to 6% and 14% of variance in WMH volume in the pooled sample and in men, respectively, which is comparatively more than the proportions of variance explained by hypertension (1%), type 2 diabetes (1% to 3%), or smoking (<0.1%).

What Are the Clinical Implications?

• Hydroxyphenylpyruvate is a potentially useful clinical biomarker explaining more variance in WMH volume than the established WMH risk factors.

• The marked sex specificities in the metabolomic associations of WMH volume add to the growing body of research suggesting that sex-specific molecular pathways underlie the associations between risk factors and cerebrovascular outcomes.

• Some associated metabolites support vessel-related pathophysiology of WMH; others suggest the involvement of myelin disruption and neuron injury.

Link | PDF (Circulation)

 

[SNT Gatchaman]

White matter hyperintensities (WMH)—areas of high intensity in the periventricular and deep cerebral white matter on T2-weighted (T2W) or T2 fluid-attenuated inversion recovery images—are among the most commonly encountered signal alterations on brain magnetic resonance imaging (MRI). The exact neuropathologic mechanisms are not fully understood, but the proposed fundamental features of WMH are loss of myelin and axons and mild gliosis. These features might arise from chronic ischemia and dysfunction of the blood–brain barrier (BBB) related to cerebral small vessel disease.

Evidence from a recent meta-analysis of prospective cohort studies indicates that WMH are of major clinical significance. [...] Hypertension, type 2 diabetes, and smoking are the key cardiometabolic disease risk factors for WMH.

The metabolomic associations of WMH, however, are incompletely understood [...] We used metabolomics technologies to provide a comprehensive characterization of variations in circulating metabolomic measures as a function of WMH volume assessed in the general population. We further explored whether these associations are independent of the key risk factors of WMH, including hypertension, type 2 diabetes, and smoking.

 

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(Statistics omitted for summary).

WMH volume was associated with lower circulating concentrations of lysophosphatidylcholines (LPCs) and hydroxylated sphingomyelins (SM-OHs). Among the studied LPCs, the strongest association was seen with LPC(22:6), which was significant in the pooled sample and in the male subsample. Among the studied SM-OHs, the strongest association was observed with SM (OH) C22:2; this association was significant only in the male subsample.

A sizable proportion of the studied metabolomic measures were circulating concentrations of lipoproteins and lipoprotein lipids (≈24% of the meta-analyzed measures). Out of the 30 metabolomic measures showing FDR-significant associations with WMH in the basic models, 12 were with measures of the lipid composition of the intermediate-density lipoprotein and low-density lipoprotein (LDL) particles (lipid composition calculated as a ratio of a lipid concentration against total lipids concentration within individual lipoprotein subfractions). Higher WMH volume was associated with higher triacylglycerol to total lipids ratio and lower cholesteryl ester to total lipids ratio in the pooled sample and male subsample.

 

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Several aspects of our metabolomic findings support a possible vessel-related pathophysiology of WMH and some suggest the involvement of myelin disruption and neuron injury. A number of the observed associations showed sex specificities, indicating that distinct metabolomic features accompany WMH in men and women.

HPP is hydroxyphenylpyruvate.

the most robust association was the positive association between WMH volume and HPP in male participants (PFDR.full.adj =1.40×10−7); the association was also significant in the pooled sample (PFDR.full.adj =1.66×10−4) and in individuals not treated with a statin (PFDR.full.adj =1.65×10−6). HPP is a potentially toxic compound derived from the catabolism of phenylalanine and tyrosine.

We did not see strong associations with phenylalanine or tyrosine and thus the association between WMH and HPP likely arises downstream from phenylalanine hydroxylase

The enzymatic alterations possibly contributing to higher level of HPP could be higher activity of tyrosine aminotransferase (TAT) or lower activity of hydroxyphenylpyruvate dioxygenase (HPD). [...] TAT converts tyrosine and α-ketoglutarate to HPP and glutamate 39 and thus higher TAT activity could contribute to lower α-ketoglutarate and to higher glutamate. In male and statin-treated participants, however, we found only a nominal association between WMH and circulating α-ketoglutarate, which was not in the anticipated direction, and no association with glutamate.

in the view of these results, lower HPD activity appears as the most likely mechanism driving the association between WMH and circulating HPP. HPD requires oxygen to convert HPP to homogentisic acid and, consistent with this requirement, hypoxia promotes accumulation of HPP. The deep and periventricular white matter, which is the predilection site for WMH, is characterized by sparse vasculature consisting of long, narrow end arteries and arterioles that are vulnerable to oxygen desaturation.

 

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SM-OH is hydroxy-sphingomyelin.

In addition to the nonlipid measures, we found that WMH were associated with several circulating lipids most notably with LPCs and SM-OHs. These associations were almost exclusively negative and reached statistical significance predominantly in male participants and, in some cases, also in the pooled sample. LPCs are phospholipids generated by partial hydrolysis of phosphatidylcholines, which are the building blocks of cell membranes [...] LPCs modulate inflammation and oxidative stress, and they may alter the integrity of endothelial membranes, including the BBB.

Similar to LPCs, the associations between WMH and SM-OHs were negative, with the most significantly associated SM-OH being SM (OH) C22:2 in male participants (PFDR.full.adj =0.042). SM-OHs are important components of myelin sheaths, which are lipid-rich cell membranes wrapped around neuronal axons, protecting the axons physically and providing trophic support, as well as increasing the conduction speed of action potentials. The negative associations between WMH and SM-OHs could point toward disruption of myelin sheaths

previous evidence suggests that low level of serum total sphingomyelin is associated with cross-sectional memory impairment.

 

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Concluding —

Although no causal associations can be inferred from the findings, they indicate that alterations in circulating metabolism are closely linked with WMH in a general population of middle-aged and older adults and suggest that the metabolomic profiles accompanying WMH in men and women may differ.