Joanna Wardlaw, MD, on Biomarkers, Repurposed Drugs, and the Future of Small Vessel Disease Treatment

Cerebral small vessel disease is responsible for roughly a quarter of ischemic strokes, the majority of brain hemorrhages in older people, and an estimated 45 to 50% of all dementias when accounting for both pure vascular dementia and its contribution to mixed Alzheimer’s presentations. Despite affecting an estimated 700 million people worldwide to some degree, it has historically been managed primarily through vascular risk factor control. Growing evidence now suggests that something more is happening biologically, opening the door to more targeted therapeutic approaches.

Joanna Wardlaw, MD, is a Professor of Applied Neuroimaging at the University of Edinburgh and one of the leading researchers in cerebral small vessel disease. She presented a talk titled “New Treatments for Cerebral Small Vessel Disease: What Does the Future Hold?” at the 2026 World Stroke Congress (WSC) in Seoul, South Korea, where NeurologyLive sat down with her to discuss the state of the field.

In a conversation with NeurologyLive, Wardlaw explained why risk factor management alone has not been sufficient to halt disease progression, what genetic and pathological studies are revealing about the underlying biology, where biomarker development stands, and what it could mean for patients if one of the repurposed drug candidates currently in trials delivers a meaningful result.

NeurologyLive: Tell us about your talk and why cerebral small vessel disease feels like such an important frontier for the stroke field right now.

Joanna Wardlaw, MD: Cerebral small vessel disease is a very common condition. It causes about a quarter of ischemic strokes and most brain hemorrhages in older people, so that’s a large portion of the stroke burden. It is also the main cause of vascular cognitive impairment and vascular dementia, accounting for about 20% of all dementias. In addition to pure vascular dementia, it’s also common in mixed dementias with Alzheimer’s disease, where it makes symptoms worse than if you just had the Alzheimer’s pathology. If you put all of that together, it’s responsible for somewhere between 45 and 50% of all dementias, which is enormous when you think about the global population.

Beyond dementia, it also causes gait and balance problems in older people, restrictions in mobility, and problems with mood and apathy that are often quite subtle. It can present through stroke services, dementia services, or medicine for the elderly, and it can also be found incidentally on a brain scan done for another reason, which is quite a common way people discover they have the condition. A rough back-of-the-envelope calculation suggests somewhere in the region of 700 million people worldwide have some degree of small vessel disease. Because it touches so many different services and presents in so many ways, the full burden hasn’t always been properly recognized.

Small vessel disease has historically been managed largely through vascular risk factor control. What has changed in our understanding of the disease that is opening the door to more targeted therapeutic approaches?

This is a really important point. Small vessel disease has well-known vascular risk factors: high blood pressure, diabetes, raised blood lipids, smoking, and lifestyle factors. For a long time, because there is an association between hypertension and small vessel disease, it was assumed that treating vascular risk factors would essentially make the disease go away. Those risk factors are important to treat for many reasons, but the actual evidence indicates that even quite intensive treatment has some effect without having a major impact on preventing the progression and worsening of the clinical features of small vessel disease. That says there’s something else going on.

What’s become more apparent is that there are genetic contributions. There are rare familial causes of small vessel disease, and the more researchers have been able to do genetic studies across large populations, the clearer it has become that weaker versions of these gene variants are distributed across the population and help explain why some people are more vulnerable. If someone has that vulnerability and then develops hypertension, they’ll get worse disease than someone without it.

Studies from multiple angles, including brain imaging, genetic studies, and human pathology, are revealing that there are abnormalities in how small blood vessels are able to react. When the brain is active and needs more blood flow, if the blood vessels can’t respond properly, that part of the brain may not get sufficient flow. The blood vessels can also become leaky and inflamed. Each of these features presents an opportunity to intervene with drugs that might reduce leakiness, dampen inflammation, or improve vessel reactivity. We’re starting to see data from trials of drugs with those modes of action suggesting there is benefit. We haven’t done large enough trials yet, but things are heading in the right direction.

How close are we to having imaging or fluid biomarkers that can reliably track disease progression and treatment response in a trial setting?

We have some reasonably good imaging biomarkers. The challenge is that they often require a more advanced brain MRI than what’s routinely available in every hospital, which means trials would have to be restricted to centers that can do that kind of imaging. So, the imaging side is reasonably mature, and we have a fairly good understanding of what brain imaging markers tell us about disease progression.

Blood biomarkers haven’t received the same attention. It’s not like Alzheimer disease, where there has been a huge number of biomarker studies. The small vessel disease field is somewhat behind, but we are beginning to see studies looking at diagnosis and progression. I’m reasonably optimistic that there will be blood biomarkers because we’re dealing with the lining of blood vessels, which is right next to the blood. You have a good chance of detecting something in the bloodstream that shouldn’t be there, or that’s present in higher amounts than normal. In another few years, we may have some quite good ones.

I also wouldn’t underestimate the power of physical and cognitive measures. Any one scan or blood test is only telling you one part of a very complicated picture, whereas the brain when it’s doing something tells you quite a lot. Tests of manual dexterity, mobility like the timed up-and-go test, and certain cognitive assessments are quite sensitive to long-term changes from small vessel disease. And with wearables now providing sensitive monitoring of mobility and gait patterns, it’s possible that digital versions of what are currently pencil-and-paper tests could become reliable markers. I wouldn’t rule them out. I think they’re quite powerful.

If even one of the therapeutic approaches currently in development delivers, how meaningfully could that change the trajectory of cognitive decline and stroke occurrence for patients?

At the moment, we have a number of drugs used in other areas, mostly cardiovascular disease, and we have limited data from clinical trials in small vessel disease suggesting that over a period of around a year, they can lead to improvements in cognitive function or less dependency by the end of that year. The size of that difference suggests it would be quite meaningful if confirmed in larger studies. And because most of these drugs are generic, outside their patent phase, they’re fairly inexpensive and widely available, not just in Europe but around the world. One of them is among the 100 most used drugs in the United States for cardiac disease, and nobody has really thought about whether it might also do some good in the brain.

If any of these widely available drugs have even half the benefit suggested by the early trial data, we already know they’re quite safe from their other uses, and they also appear safe in the small vessel disease population in the trials done so far. They could translate into clinical practice relatively quickly, because they’re already available and would need only a license extension to a brain indication rather than years of further development. We are currently running a phase three efficacy trial powered to detect improvements in cognition, dependency, and recurrent stroke. We expect to finish recruiting and complete follow-up in about two years. If it confirms the phase two results, I would expect a rapid turnaround to extending the license. Other trials are also funded and getting ready to start testing different repurposed drugs. We’re perhaps five years away from having real answers, but not twenty.

Transcript was edited for clarity. For more WSC 2026 coverage, click here.