Cardiovascular

Metabolic Markers of MRI-Confirmed Lacunar Stroke: Observational and Mendelian Randomization Analyses.

Ng W, Aghakishiyeva E, Markus H, Harshfield E • Neurology • 2026

PubMed 42721413 DOI 10.1212/WNL.0000000000218409

TL;DR

Mendelian randomization analyses identified inverse causal associations of glycine and the proportion of cholesterol to total lipids within medium LDL with two distinct subtypes of MRI-confirmed lacunar stroke, suggesting these metabolites may inform future studies of SVD pathogenesis and biomarker development.

Key Findings

Results

Observational analyses identified 211 metabolites significantly associated with lacunar stroke among 2,408 participants.

The cohort included 1,456 lacunar stroke cases (mean age 62 [SD 12]; 34% female) and 952 controls (mean age 57 [SD 6]; 38% female).
Participants were recruited from stroke centers across the United Kingdom.
250 serum metabolites were assayed using NMR spectroscopy.
Cases and controls were MRI-confirmed and hospital-recruited.

Results

Mendelian randomization identified a significant inverse causal association between glycine and isolated lacunar infarcts (ILI).

ILI was defined as 1 lacunar infarct with Fazekas grade <2.
The odds ratio for glycine with ILI was 0.704 (95% CI 0.585–0.848).
This association was identified through bidirectional Mendelian randomization using genome-wide association analysis of each metabolite.
Glycine was among the most robust and consistent associations across both observational and MR analyses.

Results

Mendelian randomization identified a significant inverse causal association between the proportion of cholesterol to total lipids within medium LDL (%C/Total in M-LDL) and multiple lacunar infarcts and/or leukoaraiosis (MLI/LA).

MLI/LA was defined as >1 lacunar infarct and/or Fazekas grade ≥2.
The odds ratio for %C/Total in M-LDL with MLI/LA was 0.541 (95% CI 0.401–0.730).
This finding was distinct from the glycine association, implicating different metabolic pathways in different lacunar stroke subtypes.
%C/Total in M-LDL was among the most robust and consistent associations across both observational and MR analyses.

Results

Five metabolites were significantly associated with executive functioning and processing speed in observational analyses.

The five metabolites were: Total S-HDL, S-HDL concentration, phospholipid (PL) in S-HDL, %CE/Total in L-LDL, and lactate.
These associations were with cognitive outcomes including executive functioning and processing speed.
These associations were identified in observational analyses but were not confirmed by Mendelian randomization.

Results

Mendelian randomization implicated genetically determined levels of omega-3/Total fatty acids (ω-3/Total FA) with two diffusion tensor imaging markers of SVD.

This association was identified through MR analyses rather than purely observational methods.
Diffusion tensor imaging markers are neuroimaging markers of cerebral small vessel disease.
This finding adds to the evidence linking omega-3 fatty acids to SVD pathology at the neuroimaging level.

Results

Glycine and %C/Total in M-LDL were identified as the most robust and consistent metabolite associations across both observational and Mendelian randomization analyses.

Of 211 metabolites showing observational associations with lacunar stroke, only 2 were supported by MR causal analyses.
The two metabolites were associated with two distinct lacunar stroke subtypes, suggesting heterogeneous metabolic pathways in SVD.
Bidirectional MR was used to investigate causality and reduce confounding inherent in observational analyses.

What This Means

This research suggests that two specific blood metabolites — glycine (an amino acid) and a measure of cholesterol composition within medium-sized LDL particles — are causally linked to different subtypes of lacunar stroke, a type of stroke caused by disease in the brain's small blood vessels. The study used a combination of traditional blood-marker comparisons and a genetic technique called Mendelian randomization, which helps establish whether a relationship is causal rather than just a coincidence, in a group of over 2,400 stroke patients and controls recruited from UK stroke centers. Higher levels of both metabolites were associated with lower odds of their respective stroke subtypes, with glycine linked to a milder form (a single lacunar infarct) and the LDL cholesterol measure linked to a more severe form (multiple infarcts or significant white matter damage). The study also found that several HDL-related metabolites and lactate were linked to poorer cognitive performance — specifically executive function and processing speed — in observational analyses, and that omega-3 fatty acid levels relative to total fatty acids were causally associated with MRI-based markers of small vessel disease in the brain. However, these findings were less robustly supported than the glycine and LDL cholesterol results. This research matters because cerebral small vessel disease is a leading cause of stroke, vascular dementia, and cognitive decline, yet its biological causes are not fully understood. By identifying specific metabolites causally linked to different stroke subtypes, this work could help researchers develop better biomarkers for diagnosing or monitoring small vessel disease and could point toward new biological pathways worth targeting in future therapeutic research.

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Citation

Ng W, Aghakishiyeva E, Markus H, Harshfield E. (2026). Metabolic Markers of MRI-Confirmed Lacunar Stroke: Observational and Mendelian Randomization Analyses.. Neurology. https://doi.org/10.1212/WNL.0000000000218409

Key Findings

What This Means

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