Dr. Steven M. Greenberg

A conversation with Dr. Steven M. Greenberg, MD, PhD, Professor of Neurology at Harvard Medical School and John J. Conway Endowed Chair in Neurology, Director of the Hemorrhagic Stroke Research Program and Vice-Chair for Faculty Development and Promotions at the Massachusetts General Hospital.

Interviewed by Kristina Shkirkova, Doctoral Candidate in Neuroscience at the University of Southern California. 

They will be discussing the article Vascular Contributions to Brain Health: Cross-Cutting Themes.” Published in the February 2022 issue of Stroke, the article introduces a series of Focused Updates articles on topics related to brain health.

Kristina Shkirkova: To set the stage for this interview, could you briefly summarize the current understanding about the importance of vascular health towards brain aging and health span in general?

Dr. Greenberg: We think of brain health as central to healthy aging. Everybody wants to live a long life, but no one wants to live it without the ability to do activities that make you who you are. There is no healthy aging without brain health. It is important to note that vascular brain health is not the only part of brain health, but it is certainly a major part. We see that diseases of the large blood vessels and the small blood vessels (the major focus of this review series) are very common as people age. So almost everybody has some degree of vascular disease with aging. It’s an interesting contrast with some diseases that are less common that cause severe illness. Vascular disease is different: It’s highly prevalent, meaning that many people have it. It’s almost unusual for someone not to have some evidence of vascular disease. The contribution of each individual vascular disease is modest, but it becomes significant when they co-occur and especially if they are added on top of the other kinds of brain changes, such as Alzheimer’s disease. It’s the combination that is worse than either one by itself.

Vascular health is not the only important part of brain aging, but it’s essential for healthy aging. What makes it a particularly attractive area for current research is whereas we really don’t have an effective treatment to prevent other forms for brain aging, we do think we have effective treatments that have a good chance of preventing much of the vascular contribution to brain aging. I think these are the things that make vascular health a central focus and perhaps the thing that we should be working on right now while other therapies are being developed for other brain disease that comes with aging.

The total amount of dementia is going up because societies (in both high- and low-income countries) are getting older. That alone is enough to drive an increase in the number of people with dementia. But if you look at each age group to see how many people have dementia, the proportion is going down, especially in the high-income countries. We still don’t have effective treatments to prevent Alzheimer’s disease, so there is a good chance that this decline in dementia within each age group is happening because of improvements in treatment of things like high blood pressure. There are also some unhealthy trends that are going on, such as increasing rate of obesity and diabetes. But there are good trends that are going on, such as the medical community doing a much better job at identifying and treating high blood pressure. Also, the rates of people having strokes are going down. It is challenging to prove what causes it, and we are all happy for any good news. But I think it is very reasonable to think that it is about better control of high blood pressure, which results in the vascular contribution to dementia, as well as the number of strokes going down.

Kristina Shkirkova: Based on the evidence provided in this Focused Update series of review articles on vascular contributions to brain health, do you believe the trajectory of vascular health could be improved or reversed around or before midlife by introducing lifestyle changes directed at attenuating risk factors contributing to vascular disease?

Dr. Greenberg: One of the things that comes across beautifully in the articles in this review series is that vascular health is a lifetime process. In the medical world, we joke that everything must happen in 5 years, because that is how long a typical grant the U.S. National Institutes of Health (NIH) lasts. But this is not a 5-year problem. The intervention to be effective might have to be started 10 years, 20 years, or 30 years before someone gets dementia. That is hard for us as a society to deal with. We want something that has effects very quickly. At minimum, midlife is the time you want to treat vascular risk factors. If such an intervention is effective in midlife, it might be even more effective if started in early life. People with obesity and metabolic syndrome at younger ages are a trend going in the wrong direction. There is every reason to think that the earlier vascular risk factors are addressed, the better. It is about playing the long game because young people have a long way to go before they are old. But they will get old, and we want them to have healthy brains. It’s hard to prove it because the study would take so long, but I think there is every reason to believe that interventions in midlife or earlier will have payoffs down the road in terms of keeping a healthy brain.

Kristina Shkirkova: For designing future clinical trials, what approaches could be implemented to account for racial and sex disparities?

Dr. Greenberg: For us as a society, much of the focus has been on affluent White people in high-income counties with too little focus on underrepresented groups like African Americans and on lower income counties around the world. It is not enough to focus on the groups that already have the most resources and most research done; this is something that we really must be able to apply in a range of settings both in the U.S. and around the world. NIH has become very aware of the issue, and they are no longer leaving it up to investigators. They are requiring people doing studies to make sure they are generalizable to all people having the diseases. In the U.S., it certainly means non-White populations and that studies identify African American and Hispanic American communities as being essential to the study so that the results are applicable to all people who suffer from the disease. Otherwise, it is bad science that will not have the public health impact that we want to have. I think the strategies for making more diverse and generalizable research happen both in the U.S. and internationally are challenging. The most effective strategy appears to be to involve members of the underrepresented communities in the design and implementation of research trials rather than a top-down approach of telling everybody what to do. For international and domestic studies, this means building partnerships that allow research to accomplish its goals.

Kristina Shkirkova: Considering recent developments in vascular health biomarkers that include imaging and blood analysis, which approach would be more advantageous to use in clinical practice, and if both, could they be combined for early diagnosis of cerebrovascular pathologies?

Dr. Greenberg: I have a particular interest here because I am part of the MarkVCID Coordinating Center at Massachusetts General Hospital, in Boston, MA. MarkVCID is a biomarkers consortium for small vessel diseases that is funded by NIH. We are particularly interested in identifying the most useful biomarkers and doing the foundational studies that will allow them to be widely adopted in clinical trials. I hope that over the upcoming years, we will have strong data that will tell us how to incorporate small vessel disease biomarkers into trials. MRI imaging has been a very powerful tool to study small vessel disease as it is related to brain disease. MRI is expensive, it is not available everywhere, and it is not a perfect tool by any means, but it has provided a range of markers that show various kinds of brain damage caused by small blood vessel disease. We hope to develop biomarkers not just for the small vessel-related injuries in the brain, but also for the small blood vessels themselves. The problem there is that small blood vessels are indeed small, at the sub-millimeter diameter level. We are increasingly developing indirect ways for looking at them, for example, measuring how the small blood vessels react to stimuli. There are other things, such as blood brain barrier and how leaky the blood vessels are in the brain. I think that if we could have a wish list, these types of biomarkers would be on that list. But I also think different biomarkers will serve in different situations. It is hard to have everybody get an MRI. As blood biomarkers get better over time, the hope is they could be applied more broadly than MRI. For MRI, you need to have a machine where the patient is, but for blood biomarker, all you need to do is obtain the blood and then the sample can fly off to the place where the test is done.

Kristina Shkirkova: In your opinion, what are the current translational gaps between basic and clinical research in vascular health that need to be addressed?

Dr. Greenberg: We want to find interventions that make a difference. We have the tantalizing multimodal interventions like the FINGER study (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) that is talked about in one of the articles. They used the approach of having multiple interventions, not just medications, but also exercise and diet. And it showed exciting results. It would be useful to know which one of the interventions matters and does it work in every setting. We don’t know exactly how they work, and we don’t necessarily need to know, but if we understand the mechanism, then it makes it more likely we could find what is the most effective and target that thing specifically. So, I think I am seeing a gap from multimodal interventions to our understanding of their mechanism. From a practical standpoint, you want to be able to tailor the treatment for the specific group of people you want to treat and to come up with the most scalable and the most feasible intervention that can be done. People probably have some limitations at how many things they are willing to do. I see that as a big issue.

Another interesting area that was mentioned in a lot of the papers is the role of brain recovery. We often think about the brain injury process in isolation, but what are the things that help the brain to be resilient to injury? We talk a lot about that with acute stroke when we discuss how well someone recovers from stroke. But we can think of the brain injuries from small vessel disease as something that continues to occur every day, every week, every month, and on and on. There is a damage aspect to it, but there is also a constant recovery process. I think it is possible that this is how some multimodal interventions work, by improving the resilience of the brain rather than reducing the injury damage. That is something that I think we could understand better and turn into therapies. The more we understand, the more we can do about it.