What Can People Do To Maintain Brain Health As They Age?
Rudolph Tanzi: Harvard Magazine
Harvard Medical School professor of neurology Rudolph Tanzi discusses how lifestyle choices can help maintain brain health during a person’s lifespan. Topics include Alzheimer’s disease and other kinds of dementia, the role of genetics and environment in health, and the importance of sleep, exercise, and diet in controlling neuroinflammation.
Jonathan Shaw: Are there steps that people can take to maintain brain health as they age? How much of age-related cognitive decline is attributable to genetics, and how much to factors that people can control? What role does the immune system play in brain health? Welcome to the Harvard Magazine podcast, "Ask a Harvard Professor." I'm Jonathan Shaw. During today's office hours, we'll speak with Rudy Tanzi, the Kennedy professor of neurology at Harvard Medical School. Dr. Tanzi is director of the Genetics and Aging Research Unit at Massachusetts General Hospital, vice chair of neurology and co-director of the McCance Center for Brain Health, as well as the Mass General Institute for Neurodegenerative Disease. He is co-author of The New York Times bestseller, "Super Brain," and more recently, co-author of "The Healing Self." In the scientific community, Professor Tanzi is best known for discovering several genes connected to the development of Alzheimer's disease, including the one that leads to the accumulation of plaques in the brain. In the journal "Nature" in 2014, he and his colleagues published their development of Alzheimer's in a dish, the first brain organoid model, the team proved that amyloid does cause tangles in the human brain. Welcome, Professor Tanzi.
Rudolph Tanzi: Thank you, pleasure to be here.
Jonathan Shaw: Declines in cognitive ability are often described as an inevitable part of aging, and yet some people remain sharp into their 90s and beyond. Is memory loss, an inevitable part of aging?
Rudolph Tanzi: You know, I think memory loss and some diminishing of cognitive abilities, comes along with aging the same way as you know, I can't play basketball anymore with a bunch of kids in Charlestown because my knees won't allow it. You know, things happen, things break down, knees breakdown, joints break down, and the brain starts to break down. All we can do as we get older is figure out how to preserve each organ, each joint, each muscle for a longer time. And that's what we work on at the McCance Center: how do we preserve and promote brain health, and in doing so prevent brain disease? That's our goal.
Jonathan Shaw: And how much of age-related cognitive decline is attributable to genetics, and how much to things that we could control potentially?
Rudolph Tanzi: It's interesting, you know, this is what I wrote about in "Super Genes." And I actually did congressional testimony on it, based on the books that I wrote, which was kind of interesting. And what I told them was, look, if you look at age-related diseases, like heart disease, Alzheimer's, etc., you see a similar pattern. About 5 percent of the genes involved have very hard-hitting mutations—mutations that guarantee the disease, and usually with early onset. And usually those disease genes where you can't do anything about them—they're you know, they're the rare ones—also tell you about the events that pathologically happen earliest in the disease. So, for example, you know, Brown and Goldstein won the Nobel Prize for finding a family with a rare mutation that gave them high cholesterol. And based on that, they proposed cholesterol had something to do with heart disease. And the first genes we found, you know, when I was a student at Harvard, for my doctoral thesis, I found the first Alzheimer's gene. I named it amyloid precursor protein, APP, because it makes amyloid. And the mutations in that gene cause a rare form of early-onset Alzheimer's with certainty, by making too much amyloid in the brain. And just like cholesterol, now we know amyloid is something that occurs in the brain a decade or two or three before symptoms. That's when you have to hit it, just like cholesterol, you can't wait to need to bypass to hit it. You have to hit it earlier. So it's very analogous. Now, if you look at the other genetics of age-related diseases, the other 95 percent, you have genes with variations and mutations that predispose you to the disease, others that actually protect you from the disease, but none of them with certainty, at least not within a normal lifespan. So, you know, if you look at the early-onset Alzheimer genes we found that, you know, have mutations that guarantee the disease by 60 years old. Well, when lifespan was 50, those didn't guarantee disease because you didn't live long enough. And so some of the mutations we know now that predispose you to increased risk for late-onset Alzheimer's, like the APOE4 variant is most common, you know, maybe when lifespan is 120 years old, that will be called completely penetrant. It's going to guarantee the disease because you live long enough. So whenever you think about, does a gene mutation guarantee a disease? You have to think about how long you live, because some might just take longer to give you the disease. But based on how long we live right now, only 5 percent of Alzheimer's genes guarantee the disease, 95 percent only predispose, which means lifestyle has a lot to do with avoiding this disease, which is why I wrote my books, which is why we have the McCance Center, because we want to teach people how to do their best to try to avoid this disease with lifestyle.
Jonathan Shaw: Right? Is there any evidence that these ubiquitous smartphone apps that are supposed to keep our minds limber actually work?
Rudolph Tanzi: You know, no. I mean, these different apps for brain function, you know, I won't mention the names of them, but there are different apps that basically teach you how to focus, right? How to be able to be more alert and focus more. And I think what's good about that is I mean, is that it teaches you how to learn things, right? Because as we get older, we learn less well, right? What does protect the brain is learning new things. When you learn new things, you make new synapses, you strengthen old synapses. And a bottom line is that across neurodegenerative disorders, Parkinson's, Alzheimer's, you name it, it's loss of synapses that correlates with the symptoms. So I like to say the more synapses you make, the more you can lose before you lose it. So you have to build up synapses like money in the bank, cognitive reserve, synaptic reserve, that way, you're more resilient. As the brain starts to break down, you have more synapses you can lose before you get into trouble. So learning new things will protect you: a new hobby, a new instrument, a new language, read some nonfiction, you know, just learn something, rather than just being entertained by a TV show or a trashy novel, right? Although that's fine, too, because it helps alleviate stress and that's another big thing you have to do. But in terms of brain games, the best thing they can do is teach you how to focus so you can learn better as you get older, I would say that.
Jonathan Shaw: I see. Now you have shown that education, while a teen I guess, actually can have an impact on brain health when you're much older, is that right?
Rudolph Tanzi: Well, you know, the more education you have, the more synapses you're building up your whole life. It's more money in the bank. Picture, you have so much money saved up and now you retire and now you're, you're spending money, well, you're going to last longer if you have more money saved up. It's the same thing with synapses. The more synapses you save up, as you get planning for retirement, the more you can lose before you get into trouble. So education, learning new things. But the other thing about education is it teaches you also how to take care of yourself better. You know, part of education, it might not even be causative, it might just be association, rather, you know, a correlation rather than causation. But if you're educated, you're more likely to be paying attention to what you need to do to take care of your body and brain. And so in some cases, education might protect you against Alzheimer's simply because that places you in a particular category of a type of person who may spend more time on health than somebody who didn't have that privilege and benefit of living somewhere where education and higher education was normal, and taking care of your health was a normal thing to think about. So you have to think about the correlation versus causation here as well.
Jonathan Shaw: Maybe we could talk about some of those specifics. What is the relationship between depression and brain health?
Rudolph Tanzi: Well, you know, it's, it's a chicken and an egg question there, you know, because as you get older, and your brain may not be working as well, or you might have some brain fog as we call it, like you get with post-COVID in some folks, the frustration, the agitation, even at the subconscious level, of not functioning the way you did, not recalling words and names the way you did, not being able to get to quick answers as you did ,can lead slowly to depression. And so we don't know if depression is a risk factor for Alzheimer's disease versus, is depression one of the first signs of the disease itself. So safeguarding against depression, keeping track of depression is important because once you become depressed, you might become isolated. You might choose to not learn new things, you might choose to not interact with people. You know, I have an acronym I use called SHIELD, right. I developed it after the third book for when I had to go on the book tour and I had to encapsulate the whole "Healing Self" book. And SHIELD: "S" stands for sleep, "H" stands for handling stress, "I" stands for interaction with others, not being isolated and depression can lead to that. "E" stands for exercise, "L" we just talked about stands for learning new things. And "D" stands for diet. So you know, that's how we kind of frame, even at the McCance Center for Brain Health, how to give lifestyle advice to folks about preserving and promoting brain health.
Jonathan Shaw: Okay, so maybe we could go through this in terms of the SHIELD acronym, but what about anxiety or stress? Are those the same thing, or are they related?
Rudolph Tanzi: Oh yeah, they're related. Look, I guess you could say the stress comes from having to separate or detach from something on which you're somewhat dependent or conditioned. So as we get older, you know, the changes that come that separate us, from loved one who pass away, or kids go off to college, a lot of stress comes from just being separated from things that you want and like. And that also causes anxiety. So if you think about, "What is fear?", right, the simplest way of, of what fear is that leads to anxiety and stress is memory of pain. That might sound weird to you. But the first memories we have as an infant are memories of pleasure, which create desire, and memories of pain, which create fear. You don't want that pain again, so your fear it. So that creates anxiety. Anxiety can come from wanting something you can't get-desire, you liked it before, you get attached to it. It can come from fearing something that you don't like, like going to get a root canal, because you had that pain before and now you remember it, so it's fear. And this is what causes stress: anything that separates you from where you are comfortable, secure, and feeling like life is okay. And as we get older, there are pathways in the brain that become more emboldened, more solidified, that can deal with change less well. So the more rigid you become, the more "my way or the highway" you become, the more trouble you put yourself in. It's important to stay flexible, resilient, plastic. And that means taking what comes without anxiety and stress.
Jonathan Shaw: What sort of strategies do you counsel people to take in order to cope with that or to help develop their flexibility?
Rudolph Tanzi: Well, you know, this was what "Super Brain" was mainly about. I'm not trying to promote my books, it's just in "Super Brain" we wrote about how you need to learn how to not identify with your feelings and thoughts. We make the point, the brain is an organ that serves you, the observer of the brain, just like your stomach serves you. You observe your stomach, "oh, I'm hungry, right?" "Yes, I am, my stomach." Right. But your brain, because it brings us feelings and thoughts, we identify with it. And we say that freedom comes when you sit on that mountaintop, I call mountaintop consciousness, and you observe, what thoughts are my brain bringing me right now, what feelings are my brain bringing me, right? So like to say, I use the example in the book, if you see a red car, you don't say, "I am a red car." No, your brain brought you the sensation of the color red and the shape of something that you know is a car, right? Now that red car drives through a puddle and soaks you with mud. And now you're angry. You're angry, "I am angry," right? Now you're not angry, your brain brought you the feeling of anger so you'll avoid next time getting covered in mud, because it's probably not good for you. But we will quickly say, "I am angry about what that car did." But I would argue in the "Super Brain," that's just as crazy as saying "I am a red car." Your brain simply now brought you a feeling of anger, versus the visual sensation of a red car. Identify with neither. Observe them. And live with them. And that's a good way to deal with stress. That's what we talk about in "Super Brain".
Jonathan Shaw: I see. So that's a kind of mindfulness, you're sort of aware of how your own thought process is unfolding.
Rudolph Tanzi: Yeah, as feelings come through, as thoughts come through, rather than identifying with them, observe them, learn from them. You know, same thing with habits, you know, it's good and bad habits that determine where you are and where you're going. Your habits from the past determine who you are right now, your habits right now are determining where you'll be in the future, and the only way you can change habits is you have to observe their roots in your brain as they occur. And I always like to say resistance is futile. Resistance leads to persistence. But you know, think about rewiring rather than resisting. We rewire your neuroplasticity by observing it and saying...You know, it's kind of like, your brain is kinda like a little kid that you're babysitting or parenting, right? If you try to control a little toddler, forget about it, right? Resistance leads to persistence. What you try to do is rewire. You try to, you try to show them the other ways to do things. You have to also teach your brain other ways to do things. You have to treat your brain like a petulant child that's always trying to get its way. And the reason for that is that your brainstem, you know, your instinctive brain which is 400 million years old, is constantly trying to get you in trouble. And your poor little 4-million-year-old brain, your frontal cortex, which is trying to tell you to chill out and be restrained. Well, who's going to win: a 400-million-year-old part of the brain or a 4-million-year-old part of the brain? It's like the the veteran and the rookie in the locker room. The veteran wins. So you have to go out of your way to put the rookie in the game, right, and control the big ape in the back who's trying to get you to do bad things. It's causing most of your problems.
Jonathan Shaw: Is there a connection between being overweight and brain health?
Rudolph Tanzi: Well, yeah, I mean, obesity of course increases risk for just about everything, right: heart disease, cancer, stroke, Alzheimer's disease. So what's good for the heart is good for the brain. That's whether it comes to diet, exercise. I mean, you know, the way to fight obesity, of course, is exercise and diet. And exercise actually reduces inflammation in the brain, it clears amyloid plaque out of the brain, it induces, as we showed in a paper in "Science" a couple of years ago it induces the birth of new nerve cells in the hippocampus, the short term memory area that's involved with Alzheimer's. And likewise diet, if you have the right diet, meaning more of a Mediterranean diet. I'm a vegetarian, I've been vegetarian since college. But if you're a vegetarian and you have a plant-based diet, that's best for the brain, because the main thing in that is a plant-based diet provides the fiber that your gut microbiome likes. So the bacteria in your gut you have, you know, trillions of bacteria in your gut, 8000 different strains of bacteria. Most people only know about the 10 or 12, they read on the yogurt label. But these bacteria are determining everything from mood to the amount of pathology in your brain as you age through the gut-brain axis. So a lot of brain health comes from the right diet, and high plant-based foods, vegetables, seeds, nuts, whole grains, less processed foods, less sugar, less fat, are all gonna be good for the brain, mainly because you're making your gut microbiome happy.
Jonathan Shaw: Did you start eating plant-based foods because of what you were learning scientifically? Or was it a choice that came from somewhere else?
Rudolph Tanzi: No, I had a vegetarian girlfriend in college. So I, you know, went vegetarian, and then I felt so much better. I was, you know, in college for a while I was kind of anxious and stressed and like a lot of people are in college. As soon as I became a vegetarian, everything was better. I just felt a ton better so I never went back. I do eat dairy. I'm not a vegan. I limit dairy, but I do eat dairy.
Jonathan Shaw: You were recently a co-author on a paper that identified irisin, I don't know if I've pronounced that correctly, but a muscle hormone as a means of conferring the benefits of exercise on cognitive function without the need for exercise. How does a irisin appear to work?
Rudolph Tanzi: Yeah, so Bruce Spiegelman at Harvard at Dana-Farber discovered irisin is what he says it's after the Greek god, goddess? Iris.
Jonathan Shaw: Okay.
Rudolph Tanzi: Irisin is a product of a protein that comes from a gene called FNDC5. And it comes from muscles. It's made in muscle when your exercise. So you're exercising and you make irisin and then it goes to the brain, and it's beneficial by inducing growth factors that are good for neurons, it induces neurogenesis. So, we had a paper, a separate paper with Bruce Spiegelman in "Science" a couple of years ago showing that exercise induces the birth of new neurons, neurogenesis, and it induces a very important growth factor in the brain called brain-derived neurotrophic factor, BDNF. We found you have to have both BDNF and neurogenesis to improve cognition in Alzheimer's mice. And then the new paper with Christiane Wrann who worked at Bruce Spiegelman, now she's at Mass General, she's a collaborator of Se Hoon Choi in my lab, showed that irisin is the other big player. So the big players are irisin, BDNF, and they're induced by exercise. And the cognitive provement comes from a combination of new neurons being born in the short-term memory area of the brain, hippocampus, which gets affected by Alzheimer's, but it also helps fight neuro-inflammation. Exercise also induces an enzyme, we have a new paper of sending out for publication soon, where we show that exercise induces an enzyme that eats amyloid. So another way to get rid of amyloid is by exercise. I emphasize this because the best thing you can do for your brain when you're middle aged, is think about what you do for cholesterol to keep your heart healthy, right? We all manage our food. We take a cholesterol med if we have to, we check our cholesterol every year as we get middle-aged or younger. Amyloid is to Alzheimer's as cholesterol is to heart disease. The amyloids accumulating in your brain, we think it plays a normal role in the brain protecting against infection, and too much amyloid then triggers a cascade of events that lead to cell death and inflammation and Alzheimer's. But that happens decades before symptoms. So, SHIELD, actually, all aspects of SHIELD help limit the amount of amyloid in your brain, just like the lifestyle measures you might take to limit cholesterol to avoid heart disease later on. So this is an analogy that'll become more and more apparent over time that people need to start realizing right now. And you know, this controversy about this Biogen drug that was approved for Alzheimer's, it just removes amyloid, but it didn't do much for people cognitively. And, you know, the good news about that is, you know, there's a lot to be worried about a drug that may not really work and be so expensive and people who can't get it might mortgage their house to get it for their loved one, but that aside, it opened the door now for all kinds of drugs. It can be cheaper and safer, that you're going to hit amyloid early in life, just like we hit cholesterol early in life. And I think that's going to go a long way for eradicating preventing Alzheimer's disease, or reducing the incidence of it the same way cholesterol meds have reduced incidence and prevalence of heart disease.
Jonathan Shaw: Are there particular forms of exercise that are better than others? And also is one's ability to exercise, necessarily compromised as you get older, something that you would compensate for with drugs or drug combinations like irisin and BDNF or other things like that?
Rudolph Tanzi: Well, it's the amount of exercise that matters. There's no set rule, right? I mean, some people say 7,000 steps, 8,000 steps, 10,000 steps. I have a recumbent bike, because my knees are bad from way too much basketball way too long, including over at Longwood back in the day. And you know, on the recumbent bike I can go as long as I want. So if do a half hour a day on a pretty high resilient level, like you know resistance, and 90 rpm. And that gets my heart rate going, and I break a sweat. And, you know, I just had my stress test, which I have every four years, you know? And they said, "Well," this was literally just this week, and they said, "You did better on your stress test this year than you did in 2017 four years ago. So whatever you're doing, you're doing it right." And it's not a ton of exercise. I mean, you know, half hour on a bike, watching some TV, it's not much to ask for. Or maybe just so an hour long brisk walk or a treadmill for 20, 30 minutes, that's that's all it really takes, but try to do it daily. But do we know exactly how much exercise benefits the brain? No, because the mice studies, these mice have running wheels. And they, they're nuts. They run all night. I mean, if you want to try to mimic the exercise that we do for mice to make them cognitively better in a human, you'd have to be like 100x Olympian, you would never get it done.
Jonathan Shaw: How important is sleep in this whole equation?
Rudolph Tanzi: I put sleep number one, my order in SHIELD would be sleep. It's a tie between exercise and diet. But sleep would be number one because it's during sleep that so many good things happen for your brain. I get seven to eight hours of sleep a day on weekdays, and on weekends I get eight to nine. During sleep, you clear amyloid, you stop inflammation, you consolidate memories, you wash your brain out. And the way it works is like every time you go from dream sleep to deep sleep, consider that one rinse cycle for your brain. We jokingly call it Mental Floss. Right? So when you go through that cycle of dreaming to deep sleep, you actually clear amyloid and other debris out of your brain, you help reduce neuro-inflammation, you induce neurogenesis, the birth of new neurons. But it's also when you take the memories that have been reinforced during the day from your thumb drive and put it on your hard drive from your hippocampus to your frontal cortex, you're consolidating memories. And even dreams have a huge role. I mean, dreams are basically movies based on real events, right, they're fiction, but they're based on real events. And it's the way your brain, it's not perfectly recording everything, it's re-imagining and casting again, a movie version of what really happened to help consolidate what you need to learn from those experiences. And it's not really a coincidence that after you dream and recapitulate so many memories in strange fictitious ways based on real events, that then you start to consolidate memories in deeper sleep. And you also start removing all of the debris and gunk that's produced while you're making memories like amyloid and other stuff. So I mean, this is all during sleep. So the more sleep you get, the better. So I put sleep at number one now for brain health. In fact I should say at the McCance Center for Brain Health, we're starting the equivalent of a human genome project for sleep, the human sleep project, and we're raising a ton of money for it. We're really digging into how to use sleep as a diagnostic for brain disease, using sleep as a therapeutic, finding out ways how to mimic the best things about sleep pharmacologically. So we're doing everything, doing a big project on sleep at the McCance Center right now.
Jonathan Shaw: Are you looking then also at genes that determine how well people sleep, or is that something beyond this?
Rudolph Tanzi: Yeah, there are genes that are gene mutations associated with insomnia and sleep disorders. But you can also look at the healthy aspects of sleep and say, how our genes changing in the brain during the times of sleep where you're consolidating memories or cleaning the brain. And then, you know, once you have gene expression profiles, thousands of genes firing and being expressed in different ways up and down, you can then search for natural products or drugs that do the same thing. So you can use, increasingly we can use gene expression profiles as an input on internet tools that say, okay, which drugs or natural products lead to the same gene expression changes as the good ones that occur during the best parts of sleep? And then you can see if you can find a drug that mimics the best parts of sleep, so that's another part of the research process.
Jonathan Shaw: Is reducing inflammation, which you've mentioned a couple of times now, the common denominator among the lifestyle connected changes that can help people preserve their brain health?
Rudolph Tanzi: It's the most important, because like in Alzheimer's disease, it starts with amyloid early on, just like heart disease begins with cholesterol. And as I said earlier, the early-onset families with mutations that guarantee the disease early in life, teach about the earliest events. So in heart disease it's cholesterol, in Alzheimer's it's amyloid. So if you want to protect the brain early on, prevent disease early on, be proactive rather than reactive, stop the triggers: the amyloid plaques, the tangles caused by those plaques. But at the end of the day, what causes the most damage in the brain that leads to symptoms is inflammation, right? So I like to say to plaque is like the match, the amyloid plaque is like a match. It likes the tangles. They're like brush fires and they spread. And it turns out you can live with those. You won't get the disease if you only have plaques and tangles, at least not within a normal lifespan. The cell death that's caused by the plaques and tangles, the brush fires, when that becomes too expansive, that's when you get symptoms. Well, what causes the excessive cell death is the triggering of inflammation. And the way it works is very simple. As neurons die in the brain with tangles caused by plaques as we age, those dying neurons are then detected by glial cells, particularly microglia, astrocytes. And those glial cells are programmed in a very primitive way. If they detect neurons are dying, it is assumed it's an infection, right? Because not so long ago in evolutionary terms, when lifespan was 25 years old, if somebody had neurons dying at the ripe age of 18, it wasn't Alzheimer's, you probably got a bad mosquito bite, and you had encephalitis. So these glial cells are your housekeepers, the same glial cells that during sleep are like Scrubbing Bubbles cleaning up your brain, cleaning up debris. If while they're cleaning they detect neurons are dying, they are instantly programmed to assume infection, even if it's not, because it hasn't been enough time between when lifespan was 25 and now 85 or 80, for them to change. So when they detect nerve cells dying, they assume it's an infection, and they have one goal now: stop cleaning house and destroy this part of the brain, because it's infected and we don't want that virus or bacteria to spread. That is neuro-inflammation. It's meant with good intentions: to protect against an infection that probably is not there, but was detected to be there because neurons were dying, but the neurons are dying because you're getting older with plaques and tangles. So if we want to help patients right now who have Alzheimer's, you have to put out the fire. You have to stop the neuro-inflammation or protect against it. It's late to the game to blow out the match or stomp out the brush fires to plaques and tangles, even though that will help prevent future fires. Right? So I worked with these two kids from Brown University, who came to me when they were undergrads, you know, on a student project of how to protect neurons from dying from neuro-inflammation, with the idea that, you can't necessarily stop the neuro-inflammation, well, at least if you stop the neurons from dying, that will feed less new neuro-inflammation because it's a vicious cycle. There's neuro-inflammation when neurons die, that causes more neuro-inflammation. So can we at least protect the neurons from dying? So we came up with a combination drug and started a company of which I'm a co-founder, so for disclosure purposes, called Amylyx. We did an ALS trial because across diseases ALS, Alzheimer's, Parkinson's, there are different ways to get there, but it's neuro-inflammation in the end that causes the most damage leading to symptoms. And so we did a trial on ALS and it worked, and we published a paper in "New England Journal of Medicine." The trial was done at the Healey Center at Mass General by my chief ran the trial, Merit Cudkowicz and her colleague Sabrina Paganoni. And now this little company with these two kids, as I call them, now they're 28 and 29 years old, are looking at a good chance of having a newly FDA-approved drug for ALS and helping people. So, if you want to help people who are suffering right now, with neurodegeneration, you got to put out the fire or protect against it. But for the future, for my 13-year-old daughter, she'll go to the doc, when she's, whatever 40, 50, and they'll say, here's how much amyloid you have in your brain already, just like we say how much cholesterol you already have. And here's your drug to bring it back down so you never get to the point of triggering neuroinflammation. We'll be proactive, not reactive. In the future, we'll look back at now and they'll say, man, can you imagine like back then, they waited for the brain to degenerate to the point of dysfunction before they even diagnosed the disease nevermind treat it. Imagine if we did that with heart disease and diabetes. It's absurd. But that's where we have to move now, away from that reactive approach to a proactive early detection, early intervention, early prediction approach, and that's what the McCance Center is aimed at at Mass General.
Jonathan Shaw: Thank you very much Professor Tanzi for your time today.
Rudolph Tanzi: Thank you. It's been a pleasure.
