Heart Brain Connection - Tim Hughes, PhD

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Welcome back to Ask Dr. Mia podcast. And today I'm excited to bring you my colleague, Dr. Tim Hughes, who is an associate professor in a department of internal medicine here at Wake Forest School of Medicine. He is a neuroepidemiologist, a new term I've learned about, really testing the complex relationship between heart and brain. So between cart... vascular and metabolic disorders and how they contribute to Alzheimer's disease, pathology, and other dementias. And he is the principal investigator of large NIH-funded observational studies and clinical trials on the vascular contribution to dementia. So welcome to the podcast, Tim. Thank you Mia, it's a pleasure to be here with you today. Absolutely. And I think I'm particularly excited to talk to you today about vascular contributions because I know there's a lot of confusion both in the lay public and also probably in the medical community about what is pure Alzheimer's disease versus what is called mixed dementia or the combination of blood vessel vascular contribution and amyloid plaques and other pathologic markers of Alzheimer's disease. But before we get into that, I also wanted to hear from you about some of the risk factors that people could potentially act upon before they ever start getting any signs of memory loss. Wonderful, happy to talk with you about it. I think you really bring up a great point first off, is that when we think about dementia, it's actually a really complex, multifactorial chronic disorder. And that sounds like a complicated series of terms, and it is, because it's a complicated condition. So when you think about someone you know who has dementia, most of the time they're diagnosed as having Alzheimer's disease. It's the most common form of dementia. but it's not the only form of dementia. What we know about the disease of dementia and how it impacts not just our function but our brain health, when we look at the brains of individuals who have dementia, 70% of them have what we call mixed dementia that you talked about. And that mixed dementia is not just having hallmarks of Alzheimer's disease pathology, the plaques and the tangles that we know so much about, but also having vascular disease. There are many forms, but the most common form of dementia is where we have vascular disease and Alzheimer's pathology together. That's 70% of the cases. And then when you look at the brains of individuals who look like they have probable dementia, probable Alzheimer's disease, 20% of them don't even have plaques and tangles. So what's actually going on there and what is this disease we're talking about? There's many different ways to get to dementia. And I've become very excited, and I think the field has, as well, about how vascular disease adds to our risk for getting dementia. So when we look at it, we have to ask ourselves what is going on with this disease that's a lot more complicated than we thought it was. And some of the best things we can find out about risk factors come from some really great work over the past few years that's summarized very well. I'll recommend to your listeners to look up the Lancet Commission Report on Dementia for 2020. Livingston and colleagues published this, and it provides a very great overview of the types of risk factors we can have and how they contribute to dementia. And among them, it goes through the whole life course. So actually our risk for dementia begins even before we're born. There are some genetics that can play into it, but overwhelmingly, the most important aspects of it are these things that happen across our life. whether it's early in life with education, middle age, with obesity, hypertension, and diabetes, or late in life, where we're developing hearing loss, social isolation, and other factors, these all contribute to our risk of developing Alzheimer's disease and other dementias. Yeah, absolutely. The Lancet Commission is a well-known journal that has looked at a number of what's called modifiable risk factors that influence people's risk of developing dementias worldwide, starting all the way from early life, which is really influenced by education. And then there's a whole lot of things that are happening in midlife, some of them including, of course, high blood pressure, obesity, alcohol, traumatic brain injury, hearing loss, and then later in life are things like smoking, depression, social isolation, physical activity, diabetes, and even air pollution. But a lot of the later life, midlife risk factors, I think of them as happening throughout the continuum before people really get into their 60s, 70s, and 80s in terms of potentially showing signs of memory loss. And today we're really particularly talking about sort of what are called the vascular risk factors, notably hypertension and diabetes or insulin resistance. So with that, I wanted to introduce the study that Tim has been heavily involved in called the multi-ethnic study of atherosclerosis or MESA. Tim, can you help us understand a little bit about this group of participants within MESA and how they contribute a lot to our understanding of vascular contributions to dementia? Sure, I'd be happy to tell you about it. You mentioned vascular risk factors, and we talked about how hypertension is so important in midlife. And there's been a lot of research that's been done over the past few years underscoring why high blood pressure. We know that is your systolic top number over your diastolic. That also is a really complicated thing. There's a lot of different factors that go into an individual's blood pressure. And there's a lot of really effective ways at reducing that blood pressure. So from studies like SprintMind, we know that if you intervene upon the blood pressure, go at it very aggressively and bring people down to having a systolic over 120, 120 over a diastolic over 80. If you're going towards those goals, you're actually reducing cardiovascular events. You're reducing your risk for cognitive impairment. mild cognitive impairment and dementia together, and it actually is helping brain structure over time by aggressively doing that. But one thing we don't know is, what is it about blood pressure? Is blood pressure the most important aspect that we can intervene upon? There's a lot of different forms of vascular disease. You could have atrial fibrillation. You could have coronary calcium. You could be developing atherosclerosis. You can actually have hardening of your arteries, starting at your aorta, all the way through your vascular tree. And so these changes that are happening underneath blood pressure, we like to call subclinical vascular disorders. And in a study like MESA, the multi-ethnic study of atherosclerosis, we focus on doing very detailed measures of your coronary calcium, your carotid, plaque counts, your stiffness of your arteries, over many, many years and even decades, we followed people. And now what we're doing with a study like this is we're focused on how do those subclinical changes that are happening underneath these clinical measures like blood pressure, how are they influencing our brain health? Are they leading to vascular disease in the brain? Are they leading to Alzheimer's pathology? We're starting to develop a picture. And it's really important that we look at these subclinical changes that are happening in our vessels because what we find is that even above and beyond our blood pressure, the stiffness of your arteries matters for the health of your brain. It's stiff arteries are associated with developing different forms of vascular disease in the brain. They're associated with Alzheimer's disease biomarkers. Things that... we thought were just pure Alzheimer's disease and wouldn't be related to vascular disorders. Stiff arteries are associated with having those risk factors as well. We're trying to understand those connections. So we do this in a couple of different ways. One, we're trying to understand, does this matter for everyone? So in study like MESA, we have four different racial and ethnic groups. We actually test in four different languages. English. Spanish, Chinese, which is Mandarin and Cantonese. And we're doing this in a large group of people who have these measures of vascular disease over time. And we're trying to make these connections. Are there certain risk factors that matter in different regions of the United States, in different communities in the United States? And also, where do we make these connections? Are there changes not just in the structure of the vessels, but also in the way that the proteins are being expressed? So we're starting to make these connections where we're able to dive down in a diverse group of people and look and see how the health of their vasculature is related to the health of their brain, and then to start to say, are there molecular connections between these? Because this is where we might get to new targets for treatment. prevention and the potential for hopefully preventing dementia in the future. Yeah, that's really fascinating. I have so many questions, but I'm just gonna pick one. One is, have you seen differences between racial ethnic groups in terms of, who are more likely to have these vascular risk factors or how are they different? Because in some ways, race is a social construct. Just curious biologically, what are some differences in the cohort and a diverse cohort that you guys have been studying. Great question. And you set up some really important things. We recognize that not only is race, but in general, ethnicity is a social construct as well. That what we're trying to do is we're trying to understand a life experience. And what we see is that the life experience of where you are right now in the context of your environment matters a lot. So we do see differences between these racial and ethnic groups. in their risk for developing vascular disorders. Hypertension, as an example, in our groups are the highest in individuals who report being black or African American. Aspects of atherosclerosis seem to be the lowest in our Chinese Americans. And so, What we're doing is we're taking a look at these vascular disorders and understanding how there might be differences and are these differences related to brain health. Coincidentally, African Americans and Hispanics in the United States are at the highest risk for developing Alzheimer's disease. These numbers are actually becoming very common and a lot of people see this reported. And what we see when we look at the pathology of Alzheimer's disease, the plaques and the tangles. These are not explaining those differences that we're seeing between racial and ethnic groups. They actually have very similar levels of the amount of plaque deposited in the brain. So we're looking now at what we've described in the past as these differences in vascular risk factors, and are they actually having an impact on brain health? Are they leading to more forms of small vessel disease in the brain and leading to more atrophy in the brain? We're just beginning to take a really detailed look at this, but what we're finding is that individuals who have higher risk factors for vascular disorders, no matter what their race or ethnicity, have more vascular disease in their brain. And this greater vascular disease in their brain increases their risk for getting dementia. So it's less about the differences between us and more about the risk factors that we carry through our lives. that inform the risk for us getting dementia later. Yeah, that's fascinating. When it comes to, let's just talk about blood pressure and the stretchiness of the blood vessels and arterial stiffening. Can you tell us kind of the relationship between the two? The reason why I ask is because I know you brought up Sprint Mind Study, which we will also include that study in the show notes. I know they, you know, in the intensively controlled blood pressure group. there was some fear that with reducing the top number of your blood pressure, that perhaps there will be less brain perfusion to your brain. But when they actually looked at it on imaging, there were actually more brain perfusion to the brain. So it's not that reducing the number necessarily means what we think it means. And I feel like that's just such an interesting area that not many of us know about. I'll be happy to talk more about that. So, Sprint initially recruited subjects that were 65 and older, and they followed them over time. And with those individuals, they were looking at how it impacts both vascular health and cognitive health. And in that study, it was very focused on that top number, the systolic. Can you bring it down? to normal levels, what you might have looked like when you were in your 20s, and does that have an impact? And you're right, one of the questions was, especially in older adults, are we reducing blood pressure too much? It appears that the answer is no, we're not reducing blood pressure too much by aggressively trying to bring people down to 120 over 80. What we see is that it had beneficial effects, not just for... physical function and our lower risk of getting cardiovascular events and even preventing deaths. But it also helped to prevent cases, new cases of cognitive impairment. When you look at the brain of those individuals, what it was actually doing is it was related to a slowing in the progression of vascular disease in the brain. which we measure by these things called white matter hyperintensities. They're very common with age and they accumulate with age. And this aggressive treatment actually slowed down the accumulation of those. The other thing that it did that you alluded to was it helped improve the blood flow in the brain. And there's this really interesting relationship between the blood flow as it comes from the heart, it travels along the vessels. and gets to these end organs. So let's take a second to talk about how that happens. You can think of your heart as an incredible muscle that squeezes and pushes blood out. It does that every single time it beats. Right above our heart is something called our aorta. It's where our vessels begin. It's very elastic, like a balloon. And the goal of the aorta is to handle this big ejection of blood out of the heart. and to smooth it out by getting bigger. It gets bigger and it helps make an even flow for blood going downstream. When we age, one of the things that happens that gets accelerated in hypertension is that our aorta gets stiff. And actually all of our arteries get stiff from our heart all the way to our fingers and our toes. That has big impact for the brain. because our brain has to be very finely tuned. Every single time one of your neurons fires in your brain, it needs more fuel. And its primary fuels are oxygen and glucose. it needs a very well-functioning microvasculature in the brain to get that interplay between a nerve firing and needing more fuel and our vessels allowing that to happen. So as our vessels get stiff, what happens is people have impairments in getting blood to the parts of the brain where they need it. So lowering blood pressure has been one way that helps to even out the flow and get it to where it needs to go. The other is working on reducing arterial stiffness. And that can happen all the way through what we call the vascular tree, from our heart all the way to our fingertips, toes, and brain. When we have hypertension, high blood pressure, what we tend to see is that when the blood is ejected from our heart, it doesn't get smoothed out. and the pulse pressure that comes out of our heart gets pushed all the way to this delicate microvasculature. So what happens there? Well, it not only increases our risk for getting heart attacks, it increases our risk for getting peripheral artery disease and our fingers and toes. It gets accelerated in conditions like diabetes in which you start to see your retinal changes, where people start to get vascular disease. It impacts kidney health. It can destroy some of the microvasculature of the kidney. It does the same thing in the brain. It destroys the microvasculature of the brain because this big pulse pressure's coming in. So in SPRINT, when they reduce the blood pressure, they actually smooth that out, and it helped perfusion. It helped blood get to where it needed to in the brain. Wow, that's fascinating. I don't think I got the connection between the elasticity and the stiffness of the aorta with what happens at the end organs or in the brain. So do those, if there is too much pressure coming through from the aorta, do those little arteries, arterioles, do they actually get destroyed by that pressure? They do, they absolutely do. The most common places we see it are the kidney, the delicate microvasculature of the eye. That excess pressure shows up there. We often look there the most to see how function is going and whether there's damage clinically, but all of this is actually happening in the brain as well. We don't look for it in the brain so we don't see it. Or we say, well, maybe that's just a normal part of aging. A lot of these vascular changes that are happening in the brain are not normal. So, one of the approaches that we're also taking, you mentioned before that we do some work in clinical trials. We've taken these observations from big studies like MESA where we see that when your arteries are stiff and your blood pressure is high, you get more damage across the organ systems that you have, including the brain. in the brain, stiff arteries make you more likely to have vascular disease in your brain and Alzheimer's pathology in your brain. We can't say that that's causal yet because these are what we call observational studies. We're looking maybe over the course of time, but we're not intervening on factors like arterial stiffness. So, that's one of the things that we're doing right now. clinical trial funded by the National Institutes of Health. We are a site, the University of Pittsburgh's a site, and Emory University are a site, where we're looking at using a factor that is very good at improving the elasticity of our arteries. And we're looking to see, will that reduce arterial stiffness? Will that reduce the progression of white matter disease in the brain? One of those important vascular factors I mentioned. and will it slow cognitive decline over time? So participants in our study are ongoing with taking this daily supplementation for two years, and we're going to see the changes and report the changes that we find between groups that are taking the active agent that's good for our vessels and hopefully good for our brain, versus this, what we call a placebo, that is essentially doing nothing to an individual. And we just watch them. So that type of clinical trial work is absolutely critical for us to understand how can we intervene upon vascular factors, and if we do, what impact will that have for our brain? That's really exciting. And where can people get more information about this study? Sorry, you froze there for a second. So we'll pause there. Get more information on that study. Yeah, so it is, you can actually see details of it on some of the NIH websites. You can find out through what we call Be Involved, which is one way that we talk about the studies that we have. But another way is to just email ACEstudy at wakehealth.edu. and one of our coordinators can tell you more about it. An important aspect we haven't talked about for studies like this is that, actually pause there, we'll come back to that piece in a second. So you can just end with. emailing. Okay. I'll send you the exact email too. I think that was it, but I didn't have it written down. So many. Transitioning a little bit from blood pressure to insulin resistance or particularly diabetes. I know we don't routinely check for insulin level and we don't routinely measure the response of your insulin to a big glucose load except in. pregnancy. In fact, I failed my oral glucose challenge test twice during both of my pregnancies, at least a one hour one and then I passed my three hour one. Yeah, how does blood sugar or high blood sugar affect our brain? That is a great question. That's a very active area of research. So we talked before about when our neurons fire in our brain, they need more fuel. That fuel is glucose and oxygen. Glucose, so you think higher glucose levels, that's got to be good for the brain, right? Well, no. Just like every other organ system and in cases of insulin resistance and diabetes, When we're unable to manage the glucose effectively in our body, it builds up over time. It glycates, meaning it binds to different proteins, and it can affect the function of those proteins. One of the ways that we test for high blood sugar is we do a fasting plasma glucose. It gives us a current measurement, and then we do a hemoglobin A1C. And that glycated hemoglobin is a good measure of how much extra glucose there has been in your system over at least the past month. And how much is it binding to something like hemoglobin, which is incredibly important for delivering oxygen to the brain. So there's been a lot of research looking at how do metabolic disorders impact brain health. There's not very clear answers at the moment. One of the things we noticed, early was that brains who are having problems with different dementia pathologies, like Alzheimer's disease, actually use glucose less efficiently. When we do scans where we can actually see what parts of the brain are using glucose, when people have atrophy in their brain and they have protein buildup, they use less glucose. What we are finding is that it's not necessarily true that our brain is becoming less efficient at using glucose. What is happening is that the brain is just using less of it, but maybe it can use other fuels. So there is an active area of research where we're looking to see, has the brain actually been switching fuels? Are there ways we can help that? So some of the different ways are to look at different metabolic byproducts that we have. Are there ways to supplement brain health through that? But one of the major drivers, and this is another area of active research, is when people have metabolic disorders, their vascular disease starts to ramp up. It's like adding fuel on the fire, having metabolic disorders. with vascular disease. So people with diabetes and insulin resistance, their stiffness of their arteries goes up dramatically. The efficiency at which their arteries function goes down and they develop more vascular disease in their brain as well. So what we're trying to understand is when you have metabolic disorders, is all of this going through a vascular pathway? Are there other pathways that are purely metabolic that can be supplemented by other types of fuels? And these are two really exciting aspects on the ways that we're approaching metabolic disorders and brain health. Yeah, that is also fascinating. Oh man. What what's something that has really surprised you in this heart-brain connection? Because I often times tell my patients that you know, what's good for your heart is also good for your brain. But I'm just curious from your research were there things that have been surprising to you? Absolutely. And you're so right about the motto that you have, what's good for your heart is good for your brain. In general, that's very true in most cases. Exercise is good for your heart and good for your brain. Eating well is good for your heart and your brain. So you can protect yourself in a lot of different ways. What's really struck me about this area is really how important vascular health is. When I started doing this research about a decade ago, the Alzheimer's world said it's all plaques and tangles, there's nothing else, that's all that matters. We're now looking at a moment where they're proposing to revise the new clinical criteria to not just include plaques and tangles and atrophy of the brain, but to also include vascular disease. Because vascular disease adds and contributes to someone's risk of getting dementia and the type of dementia they might have. We have so much knowledge. and tools out there to prevent vascular disease. We have a really great opportunity by focusing on what should we intervene on. We talked about sprint, we talked about high blood pressure, but there's ways to improve our vascular health that are beyond just blood pressure control. So the other aspect of this, we alluded to it in the very beginning when we talked about our life course. and when things matter. Vascular health matters at least in middle age, if not earlier. There are some heart studies, especially the Bogalusa Heart Study, that showed that among children with childhood obesity, they had vascular changes very early. You think that's changed their trajectory in life on how much vascular disease they will accumulate, how quickly, how early, and how many years they'll live with it. We don't yet know the impact that makes on the brain. We talked about hypertension and knowing. Your listeners now understand how important this is for middle age, so I will ask your listeners, do you know your numbers? What are your numbers? Well, first thing you have to find out is what's your systolic and what's your diastolic. Those two matter. The difference between them matters for your stroke risk. And also, do you know your numbers for blood sugar? Have you ever asked your doctor to get it checked? Have you ever had a way to check it yourself? Many people actually have metabolic disorders for years before they ever get diagnosed. The same goes with hypertension. What we often hear from our doctor is, your blood pressure's a little high, so what I want you to do is I want you to work on this, eat better, exercise more. Same thing happens with our blood sugar, right? And oftentimes, it seems difficult to make those changes. One thing that has really impressed me when you look at the literature on how physical activity works, we're not talking about time in the gym always. It's actually moving more. People who walk a few more blocks than average have better brains. when they're old. just moving more matters. It's good for your blood sugar. It's good for your blood pressure. It's good for your heart and it's good for your brain. So we can all make those little changes. Anybody who knows me knows that I walk to work every day. And that's actually an intentional thing. It's inconvenient some days, but it's something that I do as a way to integrate physical activity just walking at least into my exercise every day. Yeah, I take the stairs. Intentionally. Heheheheh. And those little things add up. And you know, I often encourage people to think about their future health like they think about their finances. What are you putting in the bank right now? And what are you investing in? If you're investing in a life full of sedentary activity and not moving, think about the consequences that may have in your future. So every little thing that we do is like investing a little bit in our future. Our future helps, not just for our hearts, not just for our blood sugar, but also for our brains. I think that's a really, really important thing that we can all think about now and think about just easy ways to move more. Yeah, I love the analogy of investing in your future. And we're not gonna have time to deep dive into cholesterol, but that's the only other major vascular risk factor we have not talked about. And I know there are issues, not issues, there are debates going on about whether low cholesterol is good or whether taking a statin is really good for your brain. And... I know there's an ongoing study about that as well, but in very few sentences, can you share with us kind of how important is, you know, high cholesterol or low, you know, good cholesterol to HDL in brain health? Absolutely. So cholesterol, there's many different ways to have different cholesterol levels. Some of it's genetic, there's familial types of high hypercholesterolemia or high cholesterol. And there's even some genetic types of having high HDL. People who have high HDL have lower risk for not just cardiovascular events, but they have lower risk for things like stroke. What we think about cholesterol and brain health. goes through this pathway, which is when people have high cholesterol, they tend to have more atherosclerosis, the buildup of these lipid plaques in their vessels. That increases their risk for getting small strokes. And so when we used to talk about vascular dementia, that's what we talked about. We talked about people who had strokes. and you could see a change before and after, and that's what vascular dementia was. What we realize now is that when you have these risk factors like high blood pressure, high cholesterol, high glucose, you're increasing your risk for getting these small strokes that you might not see. We might only be able to see them on MRI, and that's one of the aspects of small vessel disease that we look at. These are often subclinical. We won't see them unless we look for them. But anytime somebody has high cholesterol and they lower their cholesterol, they're lowering their risk for stroke. We know that. That's solid evidence. That's going to help brain health. Stroke occurs in the brain. Stroke is not usually just one big event. It's often preceded by a bunch of small events. or followed by a bunch of other events. So when you lower your blood cholesterol, you're lowering your risk for having brain damage due to these strokes, whether they be mini strokes or large strokes. Got it. Okay. And last question for people who are middle age and are interested in getting more involved in research looking at vascular health, where can they get more information to potentially participate? One of the best ways you can do that is through research match. The Alzheimer's Association puts together a research match where if you're interested in brain health at any age, you can find a study for you. We talked about SPRINT before, and we talked about the importance of middle-age. There is a plan for a middle-aged SPRINT cohort looking at reducing blood pressure and the impact that will make. So stay tuned for that. But in general, the best thing you can do is take a look and find a study that might fit for you. You can do that through Research Match. You can look at websites of your local academic medical center and find studies that will work for you. Great. Thank you so much for this really interesting conversation, Tim. And if you enjoyed this podcast, please share it with other people in your life or leave me a review on your favorite podcast platform and see you all next time. Great! That was awesome! Yeah, no, I-