The real cause of a common stroke may have been missed for decades

New research suggests that lacunar ischemic stroke is not primarily caused by fatty plaque building up inside arteries, as many have assumed. Instead, the strongest link appears to be with changes in the brain’s blood vessels themselves, specifically the enlargement and widening of arteries.

The findings may help explain why commonly prescribed stroke prevention medications such as aspirin and other antiplatelet drugs have had limited success in preventing this type of stroke.

Researchers say the results are already helping guide new treatment strategies, including the LACunar Intervention Trial 3 (LACI-3), which is evaluating drugs designed to protect and support the brain’s smallest blood vessels.

Brain Small Vessel Disease and Stroke Risk

Lacunar stroke develops when the brain’s tiniest blood vessels are damaged by a condition known as small vessel disease. This form of stroke is a major cause of disability and is linked to cognitive decline, dementia, and an increased risk of future strokes. Despite its importance, scientists have struggled to pinpoint exactly what drives the disease, making it difficult to develop effective treatments.

To investigate, researchers from the University of Edinburgh, the UK Dementia Research Institute, and international collaborators examined 229 people who had experienced either a lacunar stroke or a mild non-lacunar stroke.

Participants received clinical and cognitive evaluations and underwent MRI brain scans shortly after their stroke and again one year later. The imaging allowed scientists to assess stroke type, monitor signs of small vessel disease, and identify any new areas of brain injury that developed over time.

The team compared two different vascular changes: fatty narrowing of larger arteries and the widening and elongation of arteries within the brain.

Artery Widening Emerges as a Key Clue

The analysis showed that narrowing of large arteries was not associated with lacunar stroke or with small vessel disease. While artery narrowing was more common in other forms of stroke, it did not predict new brain damage on follow-up scans.

In contrast, artery widening showed a strong connection to lacunar stroke. Patients with enlarged arteries were more than four times more likely to have experienced a lacunar stroke.

Researchers also found that artery widening was linked to more severe small vessel disease, faster progression of brain damage, and a greater likelihood of developing new ‘silent’ strokes – small areas of brain tissue damage caused by interrupted blood supply that can occur without obvious symptoms.

More than one in four participants developed these silent strokes during the study, even though they were receiving standard treatments intended to prevent additional strokes.

New Treatment Approaches Being Tested

The findings suggest that future therapies should focus on the underlying damage affecting the brain’s small blood vessels rather than on fatty plaque in larger arteries.

Studies such as LACI-3 are currently investigating whether existing medications, including cilostazol and isosorbide mononitrate, can help protect the brain, lower the risk of additional strokes, and reduce long-term problems involving memory, mobility, and dementia following lacunar stroke.

Joanna Wardlaw, Professor of Applied Neuroimaging at the University of Edinburgh’s Institute for Neuroscience and Cardiovascular Disease and Group Leader at the UK Dementia Research Institute, said: “This study provides strong evidence that lacunar stroke is not caused by fatty blockage of larger arteries, but by disease of the small vessels within the brain itself. Recognising this distinction is crucial, because it explains why conventional treatments like antiplatelet drugs are not as effective for this type of stroke and highlights the urgent need to develop new therapies that target the underlying microvascular damage.”

The study was published in the journal Circulation. Funding was provided by the UK Dementia Research Institute (funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK), the Leducq Foundation, the Stroke Association, British Heart Foundation, Scottish Government’s Chief Scientist Office, Row Fogo Charitable Trust, Wellcome Trust, and other national funding agencies. The research team also included scientists from China and Mexico.