Lessons in Lifespan Health

Dan Nation is a professor of gerontology and medicine at USC. His research focuses on vascular factors in the brain and how they affect memory decline and dementia in older adults. He joined us to talk about studying blood vessels in the brain to identify early signs of dementia and potential therapies to treat it.

Transcript

Speaker 1 (00:01):

The variability in your blood pressure day to day, month to month, year to year, and sometimes even beat to beat–the variability in your blood pressure is predictive of dementia risk. So higher levels of blood pressure variability are bad, even if you have very well controlled blood pressure levels. And this is important because currently we only treat average blood pressure. There is no treatment for variability in blood pressure. So it's a new area that we should try to look into controlling to see if we can prevent dementia in people who have high variation, even if they're already treated for hypertension.

Speaker 2 (00:45):

From the USC Leonard Davis School of Gerontology, this is Lessons in Lifespan Health, a podcast about the science and scientists improving how we live and age. I'm Orli Belman, Chief Communications Officer. On today's episode: how Professor Dan Nation is studying blood vessels in the brain to identify early signs of dementia and potential therapies to treat it. Dan Nation is a professor of gerontology and medicine at USC. His research focuses on vascular factors in the brain and how they affect memory decline and dementia in older adults. Welcome to our podcast Dan, and thank you for being here today.

Speaker 1 (01:26):

Thanks for having me.

Speaker 2 (01:28):

I wanna start by asking you about blood vessels in our brain. Is there anything unique about the brain's vasculature system, and how did it become the focus of your research?

Speaker 1 (01:39):

Yeah, it's a great question. So there's actually several things that are unique about the brain vasculature. For one thing, just the number of blood vessels. So you might think about the larger vessels that you can see with the naked eye, but most of the vessels are microscopic. And we have so many blood vessels in the brain that there's actually one blood vessel for every neuron. So every brain cell basically has its own microscopic blood vessel. So it's billions and billions of blood vessels, and this is likely the case because the brain has an incredible need for blood flow to support its very high metabolic rate. And the brain cannot store energy unlike other tissues in the body, and so any energy that the neurons need, they have to get on the fly from blood. So there's a torrential amount of blood flow that's disproportionate to the size of the brain.

Speaker 1 (02:34):

In addition to that, blood is actually toxic to brain tissue. And so the neurons need a special environment to operate, and so that milieu has to be well controlled. So the blood contains proteins, cells, infectious agents, metals, ions–all of which, if it were to get into the actual brain compartment, would be very toxic and would cause degeneration of the brain cells, cell death. And so their brain has a special structure that divides the blood off from the brain. This doesn't exist in other parts of our body; it's called the blood brain barrier. So that has to have integrity in order for the brain to survive and function properly. In addition, because of that, the way waste products of regular cellular metabolism and so forth, any other toxins that are in the brain, the way that gets moved out of the brain is different than other parts of the body because the lymphatic system in the brain is really different because we have to have this blood-brain barrier. So for a number of different reasons, the vessels are special. A lot of it has to do with the blood-brain barrier because the separation of the blood from the brain means that all of the nutrients have to be pumped actively into the brain. And all of these, again, waste products have to be pumped actively out somehow. And so any dysfunction there could lead to the buildup of toxins in the brain, which would cause degeneration.

Speaker 2 (04:11):

So your PhD is in psychology, correct?

Speaker 1 (04:14):

Yeah, neuropsychology.

Speaker 2 (04:15):

Neuropsychology. So how did you get interested in the vascular system?

Speaker 1 (04:19):

Yeah, I actually have always studied the vascular system because I was in a neuroscience lab that was focused on relationship between behavior and cardiovascular disease and basically neurovascular function and in particular as a clinical neuropsychologist we're involved in treating patients with neurocognitive disorders of aging, like dementia of Alzheimer's disease. And so I became interested in how these neurovascular factors may contribute to those diseases and to cognitive decline from those experiences.

Speaker 2 (04:54):

This sounds like a very complex system. What happens to it as we age?

Speaker 1 (04:58):

So as we get older, most people will develop a number of different vascular changes or will be at risk for different age-related vascular diseases. The most common is hypertension or high blood pressure. As we get older, the odds of developing high blood pressure just go up and up, and ultimately if you live long enough, most people will develop hypertension at some point. The majority of people over the age 65 have high blood pressure. And so that has to do with changes in your overall vascular system that can lead to a hardening or stiffening of the arteries and development of specific changes in the way the blood vessels of the brain work, which can damage the blood-brain barrier, lead to leakage of blood into the brain, decreased blood flow to the brain. And also what we've found is that older adults, their micro blood vessels don't dilate as well, and so they need to be able to dilate in order to provide more blood flow as needed to support brain health.

Speaker 2 (06:11):

It sounds like you know a lot about what's happening and the inner workings of our brain. Have updated imaging technologies improved our understanding of the role of these small blood vessels, and what can you tell us about your research in this area?

Speaker 1 (06:24):

Yes, so brain MRI has been very useful because it's usually relatively non-invasive, and we can use MRI to actually study the functioning of these microscopic blood vessels that would be otherwise very difficult to study. And we can actually visualize some microscopic changes such as small bleeds in the brain because they have this blooming artifact on brain MR. So we can see things that are microscopic, and we can study how the blood vessels can dilate or constrict using brain MRI. And we can study whether anything is leaking from the blood into the brain using brain MRI. So there's a lot more that is happening in MRI science that we're constantly monitoring and trying to incorporate into our studies. So I think there will be further advances, and we'll be able to study brain blood vessels even better in the future.

Speaker 2 (07:19):

And when you look at brain blood vessels, are you looking , particularly, at these microscopic ones?

Speaker 1 (07:24):

Yeah, we study the blood flow through these microscopic vessels and also whether or not they're leaking the leakiness of these vessels.

Speaker 2 (07:32):

I listened to a talk you gave, and you mentioned something called a neurovascular unit. What role does that play in brain health or brain dysfunction?

Speaker 1 (07:41):

It's a relatively newer concept that sort of springs off of the fact that again, there's a blood vessel for every neuron in your brain. It becomes clear when you understand how dense the micro vasculature is in the brain, that really it can't be totally separated from the functioning of the neurons themselves. When an area of your brain becomes active and neurons increase their activity, they need more blood flow, more nutrients, more clearance of waste, more oxygenation. And so they actually send a signal to other cells that control how much blood flow is happening, how much blood flow is coming to the vessels. So the blood vessels and the neurons are connected and communicating with each other. And so it's become clear that there's really this micro organ that we call the neurovascular unit, which is comprised of the blood vessel cells themselves, the neurons and other support cells, astrocytes, pericytes. And so all these different cells work together as a unit to make sure that blood flow meets the neurons’ metabolic demand.

Speaker 2 (08:50):

And when this isn't working correctly, why is early detection of dysfunction in this area so important?

Speaker 1 (08:56):

Yeah, it's extremely important because if you think about it, when you have a problem with the blood vessel that could predate the actual injury to the brain, you can have dysfunctional blood vessels, but that doesn't mean you have any brain damage yet. You just have vascular disease. The blood vessels have a disease happening within them, but that can ultimately lead to death of the brain tissue. And in the brain, once tissue is dead, those neurons died. They're not replaced, and the brain can kind of rewire itself, but it can't really regrow that brain tissue. So the idea is if you cannot detect the blood vessel problem before the brain injury has happened, then you could intervene and prevent irreversible brain damage.

Speaker 2 (09:47):

That sounds important. How would somebody know? How do you test for blood vessel function?

Speaker 1 (09:52):

So, as I mentioned, we're using brain MRI technology. We're also working on blood tests. There's different markers people are interested in. It's still, you know, at the research phase, but we have the ability to quantify how well your blood vessels are responding to stimuli, how much blood flow you have into sensitive areas of your brain that are very important for memory and other mental functions and whether those vessels are leaking, which could lead to, again, irreversible brain damage.

Speaker 2 (10:27):

What can we do to improve our vascular health?

Speaker 1 (10:30):

So the number one thing is, well first of all to monitor your vascular health through going to see your physician so that you can catch cardiovascular risk factors early. If your blood pressure is elevated, if you have a problem with your cholesterol levels, if you're pre-diabetic or diabetic, it's extremely important that those cardiovascular risk factors are caught early and are well controlled and treated right away. If they are, they're not likely to lead to brain damage, but if they're left untreated, then you have a very high risk of this ultimately damaging your brain. The other thing is basic stuff that you would do for heart health is also good for brain health. So things like a good healthy diet, exercise. Physical activity doesn't have to be running marathons. Moderate levels of physical activity are helpful for the blood vessels in your brain.

Speaker 2 (11:31):

That's certainly a message we've heard on this podcast before: what's good for the heart is good for the brain. I think most people are familiar with the idea of high or low blood pressure, but you're looking at something called blood pressure variability. What is that, and what do we know about its connection to dementia risk?

Speaker 1 (11:48):

Yeah, so as I mentioned, many people over the age of 65 are going to have high blood pressure, and those rates just go up and up. But the research has shown that once you're over 65, if you have high blood pressure, develop high blood pressure, and as long as it's being treated, your actual blood pressure level doesn't really correlate with dementia risk very much. I mean, it needs to be treated; that's important. We know that. But beyond that, where you're at with your blood pressure as an older adult hasn't been very predictive of things like brain degeneration, dementia. But what we've observed is that, even if you are treated and even if you are treated pretty aggressively, have have very low blood pressure with treatment, the variability in your blood pressure day to day, month to month, year to year, and sometimes even beat to beat the variability in your blood pressure is predictive of dementia risk. So higher levels of blood pressure variability are bad, even if you have very well controlled blood pressure levels. And this is important because currently we only treat average blood pressure. There is no treatment for variability in blood pressure. So it's a new area that we should try to look into controlling to see if we can prevent dementia in people who have high variation, even if they're already treated for hypertension.

Speaker 2 (13:18):

And are the traditional treatments effective? Has your research revealed anything about blood pressure medications and whether they can affect variability?

Speaker 1 (13:27):

Yeah, we're just now starting to do this work. It's complicated because there's many different things that affect blood pressure variability, and we need to do a lot more research. But it's already known that medications that are longer lasting, drugs that have a longer half-life or have longer term effects, for example, those tend to be better at keeping variability low in addition to keeping your blood pressure levels low. And that makes sense, right? If the drug is wearing off, you know, after a short period of time or by the end of the day, then you would expect to have more variation between doses. And so we plan to do more research on the different types of blood pressure medicines, the classes, specific agents, and we'll call their pharmacokinetic properties, how long they last in your blood, the half-life and so forth. But also adherence to blood pressure medication if people skip a dose or they're taking it at the wrong time of day–that kind of thing can also affect blood pressure variability.

Speaker 2 (14:28):

And is this research that's still in the lab stage, or is this informing clinical practice yet?

Speaker 1 (14:36):

Well it's clinical research, so we're studying human beings, older adults from the community who are taking blood pressure medications and that kind of thing. So it should, you know, our findings will be of value to clinicians, I think. And they're very interested in anything as it relates to blood pressure medicines because they're dispensing these drugs all the time in such a common condition.

Speaker 2 (14:58):

We have talked to Mara Mather about heart rate variability in this podcast, and I know that's a big area of research for her. Is there a connection between heart rate variability and blood pressure variability?

Speaker 1 (15:11):

Yeah, they're different things, but they are connected in the sense that your body tries to maintain steady blood pressure. It's not necessarily a good thing to have your blood pressure fluctuating all the time. And one of the ways that that happens, just homeostatically with normal functioning of your physiology, is changes in heart rate can help to modulate blood pressure. So they are related in terms of your cardiovascular system, but they're distinct. High heart rate variability is probably a good thing in relation to better health, whereas high blood pressure variability is a bad thing.

Speaker 2 (15:48):

This is a little bit of a subject change, but can damage blood vessels repair or regenerate themselves? And what might this mean for cognitive decline?

Speaker 1 (15:58):

Yeah, so anytime you receive any kind of injury, including a brain injury, the blood vessels and the tissue goes through a regeneration, healing restoration process. And in this case, usually it's the branching of additional vessels off of the existing vasculature. This is a process called angiogenesis, generating new branch points off of the blood vessel. So, if somebody has a stroke for example, you're gonna have a large piece of brain tissue that has been destroyed by not getting any blood flow. There's going to be a healing process that's gonna happen there, and there's gonna be some regrowth of branches of neurons as the brain kind of rewires itself and people healing from a stroke. And that has to be supported by branching off of blood vessels. So I said the neurons are very dependent on blood flow. So they work together during wound healing. And so yes, we certainly have an interest in this process since it's likely ongoing if you have some kind of microvascular damage happening, and we wanna understand more about whether it could be of benefit or it could go wrong and potentially cause harm and so forth. So we're studying this angiogenesis process in people with cognitive impairment.

Speaker 2 (17:18):

And can you tell me a little bit about how you're studying it?

Speaker 1 (17:21):

Yes. So we have lots of different projects happening. We are studying these cells that are in your blood circulation and come from different parts of your body, and they're very important in this angiogenesis process. They can actually form new blood vessels to replace damaged or dysfunctional ones. And so we can take blood from, again, older adults in the community who may or may not have different levels of vascular damage in their brains. And we can grow these cells in a dish and try to better understand whether they're functioning well, whether they're able to form blood vessels the way they're supposed to or if there's something wrong with that process.

Speaker 2 (18:06):

Is this what you're talking about when you say growing a brain in the lab?

Speaker 1 (18:09):

Yeah, so I've partnered with a bioengineering team that grows these micro brains, little brains in a dish. And what we can do now, and this is our new initiative we just started, is we can take blood from our participants and actually grow their brain vasculature in a dish. So these brain micro vessels that we're studying with brain MRI, we can actually grow them in the dish from these blood samples because we can grow these specialized cells that I'm referring to. They'll grow blood vessels in a dish, and we can see how they function. Are they forming blood vessels that are leaking? Are they forming blood vessels that are not branching properly or have other kinds of dysfunctional properties that don't support blood flow and so forth? And then we can tie that back to what's happening with that person's brain MRI. Do they have leaky blood vessels in their brains? Do they have proper blood flow on brain MRI or not? And so by doing this process, we can actually, the goal is to develop this sort of personalized medicine approach to try and better diagnose and treat brain blood vessel problems.

Speaker 2 (19:19):

So everybody's brain grows differently in a dish depending on what you're putting in?

Speaker 1 (19:25):

Yeah, this is what we're testing. So just let me give you a concrete example. If somebody has cognitive impairment and we do a brain MRI and we see that, sure enough, they have leaky blood vessels, might it be the case that this regeneration process isn't working in that person? So we could take their blood and grow a little mini brain that has their brain blood vessels in it and see whether they're leaking or not. If they are leaking, then it suggests that perhaps there's something wrong with this regeneration process, and we can actually try out different drugs in the dish and treat that person's micro brain with different potential therapies and see if any of them work. And then that might give us a clue as to how to fix the problem.

Speaker 2 (20:07):

Wow, that's really exciting. Is there anything you wanna add or any of your other research studies that you wanna give us an overview of?

Speaker 1 (20:14):

Yeah, I think the only other thing I would wanna highlight, something that I'm really excited about that we've made a number of discoveries on and are continuing to, and we actually have some papers just now coming out, is this connection between memory decline and dementia and the functioning of these tiny blood vessels, these micro vessels. We've continued to find that the memory centers in the brain, which are the same areas that are affected by Alzheimer's disease and that degenerate in neurodegenerative disease that causes a really bad memory problem and dementia in older adults, the microvessels in those areas are dysfunctional in people who are at genetic risk for Alzheimer's. And in people who have memory problems, we found that they're leaking. We found that they don't dilate properly when we give them a stimulus that's supposed to dilate the blood vessels. And in some cases they have decreased blood flow. And so it's important because it demonstrates that there is this connection between the micro vessel function and neuro degeneration, which has, I think, eluded the research committee for a long time. We've known that there's a connection between vascular disease and neurodegeneration, but that's something I'm very interested in unpacking.

Speaker 2 (21:33):

Just to follow up on that, I know we hear a lot about the plaques and the tangles that are associated with Alzheimer's disease. Where does the vascular system come into play with this? Is there a connection?

Speaker 1 (21:44):

Yeah, so the way we normally think about Alzheimer's disease is that it has, as you mentioned, these two proteins that build up. You could form the plaques and the tangles, but also ever since Alois Alzheimer first described the disease, he noticed that there were problems with the blood vessels, a condition called cerebral amyloid angiopathy, where there's also a buildup of toxic proteins in the blood vessels. And it's been noticed again over the decades that a lot of cardiovascular risk factors are also risk factors for Alzheimer's, but no one was able to quite figure out how the blood vessel changes relate to Alzheimer's disease. And I think it's only just now that we're able to study these micro vessels with newer technology, that we're understanding that the micro vasculature is probably where this link is occurring. And what we’ve found is that there's a connection to the tangles, the tangles that are happening inside the neurons that lead to degeneration of those neurons. When you have microvascular dysfunction, you tend to see that kind of degeneration happening.

Speaker 2 (22:52):

Wow. This is a really interesting window into a whole new research direction that we haven't learned about before. So thank you very much for joining us today and explaining it all to us.

Speaker 1 (23:01):

Thank you.

Speaker 2 (23:03):

That wraps up this Lesson in Lifespan Health. Thanks to Professor Dan Nation for his time and expertise and to all of you for choosing to listen. Join us next time for another Lesson in Lifespan Health, and please subscribe to our podcast at lifespan health.usc.edu. Lessons in Lifespan Health is supported by the Nay Center for Healthspan Science.