In the UK alone, roughly 100,000 people suffer a stroke each year. A quarter of these are lacunar strokes, which occur when small blood vessels deep inside the brain become damaged or blocked. Despite affecting tens of thousands of lives, the precise biological causes behind small vessel disease have historically been under-researched.
In a new study published in Neurology, the medical journal of the American Academy of Neurology, scientists from the Stroke Research Group in the Department of Clinical Neurosciences at Cambridge identified two distinct blood markers—or metabolites—that correspond to specific patterns of brain damage seen on MRI scans:
- Glycine: Lower blood levels of glycine, a common amino acid, were linked to a 30% increased risk of suffering a single, isolated small stroke deep within the brain.
- Medium LDL cholesterol: Lower proportions of cholesterol contained within medium-sized ‘bad cholesterol’ particles (M-LDL) were linked to a 45% increased risk of suffering multiple small strokes and widespread damage to the brain’s white matter.
While cholesterol is essential for building tissues and making hormones, it travels through the bloodstream wrapped in protein-fat packages called lipoproteins. The team found that the exact balance of cholesterol inside medium-sized packages matters significantly for brain vascular health.
To uncover these links, the researchers analysed blood samples and MRI scans from 2,408 participants—1,456 who had experienced a confirmed small vessel stroke and 952 healthy controls. After screening 211 blood markers, they cross-referenced their findings with genetic data using a technique called Mendelian Randomization. This allowed the team to evaluate whether the blood markers actively contribute to the disease rather than being a byproduct of it.
Dr Eric Harshfield, Senior Author of the study, said:
“We took a dual approach to check the evidence, combining direct observations from MRI scans and blood markers with genetic analysis to test for a causal relationship. This combination builds a strong case that these two blood markers are directly involved in driving distinct types of small vessel stroke.
“This opens up exciting new avenues for more accurate, targeted diagnoses and tailored treatments. In the future, clinicians may be able to look at a simple blood test to see precisely what type of small vessel disease a patient has and how it is progressing.”
Professor Hugh Markus, Chief Investigator of the study, added:
“Small vessel disease is a leading cause of both stroke and vascular dementia, yet for years we have lacked precise tools to track how it develops in individual patients. These findings give us crucial new insights into the biological pathways behind different forms of small vessel damage in the brain.
“While these results are a major step forward, patients should not make any changes to their healthcare of diet based on this study just yet. Further research is needed to understand the exact mechanisms at play. The next stage is to explore how these markers can be used in clinical trials to develop personalised preventive therapies for patients at risk.”
This work was supported by the British Heart Foundation, Cambridge BHF CRE, Cambridge NIHR Biomedical Research Centre, Alzheimer's Society, Wellcome Trust, and Stroke Association.
Notes to Editors
- Reference: The paper “Metabolic Markers of MRI-Confirmed Lacunar Stroke: Observational and Mendelian Randomization Analyses” is published in Neurology (https://www.neurology.org/doi/10.1212/WNL.0000000000218409).
- Authors: The study was conducted in the Stroke Research Group in the Department of Clinical Neurosciences at the University of Cambridge, led by PhD student Wen Hui Ng (first author), Professor Hugh Markus (Chief Investigator), and Dr Eric Harshfield (senior author).
- Sample size: 2,408 total participants (1,456 lacunar stroke patients, 952 healthy controls).
