#257 ‒ Cognitive decline, neurodegeneration, and head injuries: mitigation and prevention strategies, supplements, and more | Tommy Wood, M.D., Ph.D.

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode I'll explain what those benefits are or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest this week is Dr. Tommy Wood. Tommy is an Assistant professor of Pediatrics and Neuroscience at the University of Washington. Tommy's research interests include determining how multiple types of brain injuries can impact brain health across lifespan, as well as developing easily accessible methods with which to track health performance and longevity in both professional athletes and the general population. Additionally, Tommy has acted as a performance consultant for professional athletes in a dozen different sports and most recently worked with a number of Formula one drivers through his work with HINSA Performance, which is how Tommy and I met about five years ago. He also serves as an Associate Editor of the Wiley Journal Lifestyle Medicine, is a founding trustee and Director of the British Society for Lifestyle Medicine, and works with a number of digital health companies for charities that focus on how lifestyle and the environment can affect long term health and chronic disease. In this episode, Tommy and I focus our conversation on the brain, although we do also pepper in a few conversations around F1, given Tommy's mutual interest with mine. First, we speak about age and age related cognitive decline. We talk about what cognition and cognitive decline is, including a discussion in depth around memory, reaction time, executive function, memory retrieval, and more. We speak about the root causes of age related decline and look at cognitive demand, including how we should think about distractions and multitasking. From there we look at what skills are needed to avoid such a sharp age related decline and the benefits of different types of brain stimulation. We then talk about different theories on the different types of pathology in dementia and neurodegeneration included in this. We speak about the lifestyle factors that can help prevent dementia and the importance of muscle. We also look at various supplements that can help with the prevention and survivability of dementia. We end this discussion talking about head injuries. We speak about what a concussion and a traumatic brain injury are and what the various symptoms are, and ultimately what are the things that someone can do to minimize the severity of these. So without further delay, please enjoy my conversation with Dr. Tommy Wood. Hey Tommy, good to see you again. It's been, gosh, about six months since I last saw you at Coda, which of course we'll talk something about why you and I would run into each other at Coda, given our mutual interest in Formula one. But there might be some people listening to this who aren't familiar with you or your work, though it's certainly been referenced and you've been on a number of podcasts. So why don't you give us a little bit of your background and we'll kind of go from there. Sure.

I do have a varied experience and background, which I think is useful for the bunch of things that I do, but also sometimes slightly confusing because people will know me from one arena but not know the work that I do elsewhere. I'm an assistant professor of Pediatrics and Neuroscience at the University of Washington in Seattle. The majority of my work there is in basic animal pre clinical research in brain injury. We look at ways to treat the injured newborn and pediatric brain and we also do some work in traumatic brain injury. But before I got to that point I trained as a medical doctor in the uk. I worked as a doctor in central London for a couple of years before I did my PhD in physiology and neuroscience. So though I'm not a registered medical doctor, currently I don't have an active medical license, I do have medical training and that sort of helps inform a lot of the work that I do alongside that sort of formal training pathway. I spend a lot of time working with athletes. I was an athlete myself. As a student I spent some time coaching athletes, particularly rowers, and that was my main sport. And then later on during my PhD and when I was doing my postdoctoral work, I worked with a company that worked with athletes trying to improve performance or their overall health and their longevity in sport. That was probably the main thing that we really saw a lot of people wanting to focus on. So I have this kind of track along the side where I've worked with athletes in various ways and then through that got to working with Formula One drivers in particular through a company called Pincer. And I know you've had our good mutual friend Luke Bennett on the podcast before. So that's kind of where I do some additional work is in athletic performance and health and in addition to that also have some interest in long term cognitive functions. So we look at how the brain responds to Injury, we look at how to repair that or mitigate injury processes. But what I'm really interested in is how do all these things tie together so aspects around lifestyle and the environment affect how your brain functions throughout your entire lifespan. And so I work with some dementia charities in the UK related to that. And I'm also founding director of the British Society of Lifestyle Medicine, so particularly interested in how we can use lifestyle to improve population health.

Thanks, Tommy. That makes a ton of sense, hopefully for people now to understand the varied nature of your, both your skill set and your interests. So let's just start by diving into cognitive decline. And I defer to you, Tommy, of how you want to do this. Would you like to do this starting with the pathologic cognitive decline vis a vis dementia, or do you prefer to talk about it through the sort of more ubiquitous age related cognitive decline?

So we can start with age related cognitive decline, because that's pretty well described. So if you look across large population sets, you'll see that with increasing age, you see a pretty linear decrease in standardized cognitive function. And that's across all the different types of ways that you can measure cognitive function, aspects of executive function, working memory, except for one type of cognitive function, which is historical memory. And that's probably because of the way that those memories are encoded. They're sort of moved from the main memory storing machinery to. And they're kind of spread throughout the cortex and they're sort of protected from some of the changes that happen as we get older. But in general you just see this steady decrease in cognitive function as people get older. If you then translate that to what we might call some kind of pathological cognitive decline, which would then lead into frank dementia, which is a long term loss of significant cognitive capacity or cognitive dysfunction, then you might see an accelerated trajectory. So there's some period of what we call mild cognitive impairment, which you can put diagnosed with some standardized cognitive tests, and then eventually that will continue into frank dementia, which there are many subtypes, but the one that probably people are most familiar with and are most concerned about for themselves is Alzheimer's disease or Alzheimer's dementia. And there are probably multiple things that drive both of those paths. But in some individuals there's this accelerated decline that then ends up in then having the diagnosis of dementia.

Tommy, let's go back to the beginning of that and just make sure that we've given people a real sense of what cognition actually is. One of the most common things I hear from my patients is some sort of complaint around memory Just yesterday I was talking to a patient and he noted the fact that he had been recently remarried. He was very happy about that, but said, you know, one of the unintended consequences of getting remarried is he, he just inherited like a hundred new people in his life because all of the folks who, you know, were his wife's side of the family and her friends and stuff are now kind of a part of his life. And he said, I can't remember their names. It's the ability with which I can meet a person, remember their name is decidedly different from when I was 20 years younger. So he's in his late 50s, contrasting this with being in his late 30s. So obviously that's one component of cognition. It. It, by the way, is hands down the one I hear people most complain about. I don't hear many people complain about decreased executive function, decreased processing speed. I would suspect it's because maybe most people aren't pushing those to their limits and, or we don't have as readily available tools to internally discern decreases in that. But can you just expand more broadly on overall this, both the depths of cognition and what it entails, but also this phenomenon that I'm sure the moment someone hears what you do for a living, they're probably right up to you at a party giving you the same complaints.

Absolutely. And it's very difficult, actually. So you can define these domains of cognitive function. You've essentially already defined them. Executive function, which is usually around complex decision making. But for the average person, it might be, you know, that time when you think about saying something, but then you realize it's a bad idea to say it. That's executive function. That's the. Your prefrontal cortex is jumping in and saying that's a really bad idea, even if it sort of flashes through your mind. But then you have various aspects of short term and long term memory, processing speed, reaction time is probably important as well. However, when you talk to individuals about cognitive function, they have their own things that they want to be good at. Right. So it's very personal from an individual. Yes. We can use a standardized battery of tests and that's what's done clinically. But there's usually some aspect of function that they notice is declining over time or that they want to be better at, and then they can sort of put focused attention into improving that. And I believe that you can improve that pretty much any stage of life. So that's part of it. And you mentioned memory, and of course this is something that the people will mention the most and will notice in themselves. But there's actually two different parts to memory. And it's different probably in most people, even in the setting of sort of standard age related cognitive decline. And in those who have some kind of pathological cognitive decline. The first part of memory is encoding that memory in the first place. The information comes in and your brain signals through acetylcholine and other neurotransmitters to actually say, this is something that we want to and recognize and store. And that's the process that seems to be particularly lost in those with pathological cognitive decline. That's why things like cholinesterase inhibitors were and are still used in Alzheimer's disease, because that helps to bolster some of those encoding processes through acetylcholine signaling.

And this takes place predominantly in the hippocampus.

Yes, that's where a lot of the process starts. But over time, you get consolidation and these memories may get moved around. Particularly, like we talked about historical memory, they get shifted throughout the neocortex, which is basically the rest of the outside of the brain. The other aspect is retrieval. There's information in there, and it's getting it out. And retrieval speed is something that seems to slow down with age. But part of it, you know, often we think of this as pathological. Part of it may be that over time you just accumulate more information. And the more information that's in your hard drive, the harder it is or the longer it takes to bring out a certain piece of information.

Yeah, this is sort of the argument that Arthur Brooks used, that as we're aging, as you add memories, you're creating volumes in a library. And the more volumes in the library, the longer it takes the librarian to go and get the specific reference they're looking for. How can we figure out the relative contribution of library size versus librarian speed when it comes to accessing these memories? Because I guess this is another maybe way to think about that. But the example that resonates for me personally is I either meet somebody and can't remember their name, but five minutes later I can, or I have an idea, I want to say something about it, and at the last minute I can't remember, but then 10 minutes later, I kind of remember. So. So it's not that it's not there, but, boy, it took me a long time to get it.

So I think in reality, probably very difficult to pass all of these out. And so I don't think we could pretend that we know exactly the relative contributions. However, some of this is certainly affected by other factors. And that's something that you can take into discussion with, say, individual patients or individuals who are concerned about their memory. So it seems like sleep impairment or some kind of sleep deprivation or suboptimal sleep impairs retrieval. So then that could maybe open up a discussion about sleep. Subjective stress seems to also play a role here. So I think some of it is accepting that your library is larger, and some of it is thinking about other factors that may be impairing or allowing for that process to be suboptimal, such that retrieval is harder. Another part that comes into play here, which is also important, and it falls into that same line of thinking, Is that as your library gets bigger, your librarian becomes more selective in terms of the things that they want to actually put on a bookshelf. So imagine as you've met hundreds of people in your life, thousands of people, you add 100 new people. It's very easy to say, do you know what? The first time I meet this person, I may never see them again. So maybe it's not actually worth encoding that memory. And you become more selective in what actually gets stored. So that may be part of it as well. And these are not necessarily pathological processes. These may be your brain doing its normal job of, well, how do I figure out what's worth storing? And then how do I retrieve what I've decided to store?

This may be a question that goes beyond your level of expertise. So I apologize if I'm asking you something outside of the scope. But I guess, what is a memory physically? And why is there a finite amount of storage? So if I. If I have an understanding of why a hard drive is finite, and if I only have two terabytes on a hard drive and I keep adding video to that, eventually, at some point, there is no more storage capacity. I don't think I have enough of an understanding of what a memory is and why it would therefore have a physical constraint.

So there have been, and I will absolutely agree with you, this is beyond my area of specific expertise. I know that this is a topic that is hotly debated, where some people have said that comparing human memory to a hard drive is essentially, it's a complete fallacy. It's nothing like that. We use it because it's something that we can understand. It helps us sort of apply a very complex process to our own thinking and understanding of how our brains might work. But in reality, that is not how memories work. And there shouldn't be a limit on capacity in the same way that there is With a physical hard drive, however, you might still understand that there are probably still a finite number of things that your brain will choose to encode and store for the same reasons that you only want to have the information that's probably maximally useful for your survival, for want of a better way to think about it. And then that puts some constraints on how the system sets up what it decides to store and then retrieve.

My 8 year old son last night was asking me these questions. It's amazing when kids ask questions you can't understand, you can't come up with an answer to. And he was asking me where the memories were in his brain and how they get there. And I'm like, God, these are really good. Like when I was 8, I wasn't thinking of great questions like this. So anyway, it's disappointing that I can't answer my child's questions. Okay, so we've established that as time goes on, presumably two things are working against an aging individual. One of them not pathological one pathological. So the non pathological is you just have a greater reservoir of memories and your brain might be selectively choosing how to prioritize new encounters and new memories with some understanding that the denominator keeps growing and I have to be selective. But there's also, as you said, or I think as you're implying, there probably are some pathological changes. And whether we use the term pathology or not is probably controversial, but there are some age related changes that are occurring that are also, for lack of a better thinking, in our analogy, slowing down our librarian, reducing our librarian's vision, you know, some way that makes it actually more complicated for us to do these things. What do we think is at the root of that age related decline that is specific to be it retrieval, computational cycles, processes being, executive function, all of these things that we would all prize as important pieces of cognition.

So the way that I think about it is that we know with aging we tend to see a decrease in size or atrophy of the frontal and then the temporal, particularly the medial temporal parts of the brain. And the medial temporal lobe is where your hippocampus sits, as well as some parts of the cortex around it that support it, like the para hippocampal gyrus and the entorhinal region. And there are multiple schools of thought of why those areas of the brain may be particularly vulnerable. Some may be because of their specific function in memory or because they're deeply involved in the initiation and sort of the continuation and structure of sleep, which is obviously Very important for memory consolidation and also various processes of recovery and repair. There's also, if you think about the whole number of things that your brain is exposed to, those areas of the brain seem to be particularly susceptible to negative outside influences and then also susceptible to beneficial supportive processes, like actually putting greater demand on those areas of the brain such that they respond and increase in their function. So when I think about the various buckets of things that are required for a healthy brain, for want of a better phrase, they are around supply, vascular supply, supply of metabolic, energetic substrate. There are important things around structure and function. This could be structure related to neuronal membranes. So the importance of, say, DHA omega 3 fatty acids, which are concentrated in synapses, they're very important for communication between neurons. Then mitochondrial function as an important part of that, then you might think of actually placing a demand on those structures. In most aspects of biology, the function of an organization is proportional to the demands placed on it. So you increase capacity, but then that also requires some period of recovery, and that's where sleep and other things come into play. Plus you might want to avoid negative outside factors. So if we think about dementia, we know that there's some risk associated with things like smoking, potentially air pollution. Chronic inflammatory or infectious conditions like periodontal disease seem to be associated with it. So you want to have this supply of substrate, you want to have good function, you want to make you allow that area to rest and recover. You want to avoid things that then may impact those processes. And then sort of what I think is driving a lot of this is the amount that we actually ask those regions of the brain to do which does decline naturally over time, based on how we currently structure our lifespan.

So of all the things you said there, I think the one that we're going to click on first, I guess, would be this idea of demand and what we ask of the system. So in certain areas, as you point out, it's pretty intuitive. You cannot maintain muscle mass without putting the muscles under significant demand. That is so strenuous that you wouldn't be able to maintain it indefinitely. Right. If I look at the workout I did this morning, I wouldn't be able to do that to my muscles or to my heart indefinitely. You can do it for a few hours, but as you point out, if nothing else, through sleep. But even more than that, there are just days when you wouldn't push that hard. In other words, you sort of think of exercise as a hormetic stress. Now, I haven't thought about it this way. But there are certain organs for which I would guess that that's not true. Right. I mean, does the liver need to be stressed? Do the hepatocytes need to feel the insult of ethanol to otherwise perform? Well, I guess I haven't thought about it through the lens of kidneys and the liver and stuff. What do we know about other organs and their need to do what say, the heart does or skeletal muscle does?

I've thought about the liver in particular, and I think you can say that the case holds, particularly with alcohol exposure as the example. That's what you said and that's what I think of as well. Not that the liver doesn't function without alcohol exposure, but if it wants to optimally deal with a certain type of, of product, say ethanol, it wants to metabolize it, then we know that with chronic alcohol exposure, before we get to the point where we damage the liver, you see an upregulation in SeizcoRome P452E1, you see an upregulation in aldehyde dehydrogenase, you see an upregulation of mitochondrial function and metabolism to regenerate nad, which is sort of the rate limiting step for alcohol detoxification. So, yes, if you stress the liver with alcohol, it will upregulate its function in order to have a greater capacity when the next drinking session occurs. So I think there are sort of parallels across multiple organ systems.

Yeah. And just to make sure listeners aren't hearing this and thinking, oh, he's telling us to drink more, to drink more. No, I think what you're saying is we would all agree that the health benefits of alcohol are none. But you're saying before you get to destroying your liver with alcohol irreversibly vis a vis cirrhosis, if your goal is to be able to drink two drinks a day, you have to drink daily. Like you're going to have a better job tolerating two drinks if you occasionally have a drink as opposed to if you never have a drink. I mean, that's sort of what you're basically saying.

Yeah, that's right. And so if you want an organ system to function in a specific way, so you want your brain to function, improve its function in a specific domain, or you want your body, your skeletal muscle or your cardiovascular system to function better in a specific domain, you want to train for a marathon, or you want to be a competitive powerlifter, you apply a relevant stressor that's like you said, it's hormetic. And you give time to Recover and adapt to it, and then you get an increased capacity later. And so I think that that's very relevant for the brain. But I might use exercise as a way for people to better understand it, because you can kind of see that happening. But then to kind of draw that analogy out, you might say, okay, there are other organ systems where there's evidence that that's the case as well.

So let's go back to the brain and talk about what might be a difference between kind of a positive versus a negative demand. So I'm sure most people listening to this podcast right now are under some cognitive demand. We're not just sitting here idly shooting the breeze. We're talking about stuff that, for most of us, requires some thought, some concentration, to pay attention to this. So is listening to this podcast for different people producing different levels of cognitive demand, for example, depending on their level of familiarity with the subject?

Yes, absolutely. And again, I think that the idea of cognitive demand is relative to the individual as well as what they want their brain to function best at. However, when we think about cognitive demand, I think there's multiple different ways that you can come at it. So when I think about generating skills, or maybe just brain development more broadly to start with, you might think about how does a toddler interact with their environment such that they're developing motor skills, language skills, social skills, and it's often this concerted effort for a short period of time where you are right at the limit of your current capacity. Being able to stand, being able to walk, being able to climb a tree, being able to pronounce a certain word. And then maybe you could put a timeframe on it. Maybe it's somewhere between 20 or 30 minutes, something like that. Adults may be able to do this for longer right at the edge of your skill set. And then probably there's some failure in there, because the process of failure sort of upregulates the processes of focus and attention as well, up to a point, before we get frustrated, and then there's some rest and recovery. Your toddler is going to sleep a bunch after they spent a lot of time exploring the environment, trying to improve their motor skills. And I think that kind of provides an idea of the type of focused attention that you put into something that then drives plastic reorganization, which is what we care about. We want to try and drive an increase in functional capacity in some domain of cognitive function. And so it's probably going to be something that looks like that. And there are benefits to continually doing things at the level of your Current capacity. Right. If you're an athlete, you're not always pushing the boundaries, you're not always doing a redline session that drives a bunch of adaptation. And I think that the brain is similar, but that's very different from how most adults perform in their day to day work, where yes, it's very. It feels cognitively demanding, but you're multitasking task switching, so you're never providing focused attention on a specific subject. And you're also not really providing that stimulus to increase skill in a specific area necessarily. Even though you feel busy, even though something feels cognitive demanding. I don't think that those stimuli are the same in terms of what's driving a functional change in some area of the brain.

Yeah, it's a very important point you raise. And it of course always begs a question that I have when people tell me, or when I feel this way myself, that I just can't remember things. I'm just not as facile cognitively. And I always just wonder where distraction and lack of focus fits into the mix. So are there any kind of heuristics for what is too much task switching? What is too much distraction? Because as you said, you feel very busy sometimes. And I actually went through a little bout of this yesterday. I was really trying to get a lot of things done. And then one more thing got put on my plate and I had this window of 10 minutes where I accomplished literally nothing by toggling back and forth between three different emails, text, WhatsApp and a document I was trying to work on. And I just couldn't get anything done. I mean, that's. To be that debilitated is pretty unusual for me. But in that 10 minutes I accomplished exactly zero. I would have been better off for 10 minutes literally just walking around the house or walking around the block. So clearly there was sort of a threshold there. But do you have any way to think about what that looks like and where you've crossed a line into being busy and unproductive rather than busy and productive or focused and productive.

I would probably make the argument that humans in general cannot multitask in the way that you describe it. And again, we can sort of break this out. There are probably two different types of multitasking. One is the automatic performance of learn subroutines that kind of just happen and you could do multiple of them at the same time. So say you're a dancer and you're running subroutines, the steps you've learned, interacting with a partner, listening to the music you are technically multitasking, but those are all learned subroutines that are essentially happening automatically or subconsciously. What you're describing as multitasking is that process of focusing on one thing, then another thing, then another thing. And we know that there's a loss function in terms of the time it takes to get back onto a new task from the previous task. And it's something in the order of people have said 20 something seconds for you to refocus onto something. So say you're switching your focus every minute or two. The amount of time you actually have to focus on one specific task is dramatically reduced because a significant proportion of that is just spent with your brain figuring out what it is you're asking it to do. So in that setting, say you're doing things that allow you to enact learned subroutines in your work. You could probably do that continuously and there's less of this sort of stressful demand on your attention. But if you're needing to directly focus on multiple things at the same time, then switching from one to the other, I would argue that the majority of people cannot do that well, even though they may think that they can.

Yeah. One way that I think about this in terms of exercise is if I'm doing a steady state aerobic efficiency, we call it a zone 2 workout on a stationary bike, I can listen to a podcast and an audiobook and be completely focused on it. I can still manage to be on a bike and pedal. I don't have to worry about traffic or anything like that. And I can be focused. But if I'm doing a higher intensity cardio workout or if I'm lifting weights, I can't listen to podcasts and books. Those tasks just demand a little bit more of my attention, either to not get hurt or just to focus on the movement. In other words, they're not as presumably automatic as just holding 90 RPM at a fixed wattage. Riding around. Would you say that that's kind of an example of something that's really automatic versus something that's just a high enough order of processing where you can really only do that one thing?

Yeah, I think that's a good way to think about it. And more broadly, I think that traditional work based multitasking is probably the point where there's this biggest gap between perceived demand and the amount of beneficial cognitive stimulus you're actually getting. And it reminds me of something that a former colleague of mine at Hinser, James Hewitt, he also used to be a professional cyclist and he Calls this the cognitive middle gear. And it's this point where effort is high, but sort of the end product is minimally useful. If you can think about athletes who may go out and thrash themselves at threshold for like an hour and do that every day, it's very hard. It feels really hard. But in terms of physiological adaptations that improve performance, there's a big gap between how hard it is and benefit. And I think this kind of multitasking is the same.

Yeah, it's a physiologic no man's land.

Exactly. Yeah.

Yeah. It's too hard to give them the wide aerobic base and not hard enough to give them that peak performance. Well, this is actually kind of a nice, quick way to segue, and I want to come back to this, but just let's talk about Formula One for a second. So you and I have been fans of this sport for a very long time, but I think a lot of people listening to this have become fans of F1 through Netflix's Drive to Survive series. Of course, if you're listening to this and you don't know what Drive to Survive is, I recommend you go back and watch the last two seasons at least. But I think anybody who's watched this sport will appreciate how much they need to be able to do while driving. And on a personal level, this is something I can relate to because I spend a lot of time in a car and in a simulator, and I am nowhere near being able to do what a driver does. So for folks to get a sense of this, first of all, they're traveling at speeds that are simply unbelievable. Right. Their straight line speed is 200 to 220 miles an hour, depending on the setup they have for that race and the amount of things that they have control over on this computer that masks arrayed as a steering wheel in front of them is unbelievable. Right? So between every corner, they're making some adjustment. They're switching the brake bias with one knob, which shifts the emphasis or force between how much brake is on the front wheels versus the rear. They're altering the slip angle of the differential, which is allowing inner wheels versus outer wheels when they're going around corners to move at different relative speeds. They're obviously adjusting drag reduction system when appropriate. They're adjusting access to battery power if they're passing or overtaking or trying to defend. There's simply no shortage of things. Oh, and by the way, they're pushing a radio button to talk to their engineer, who's talking to them the whole while. So I Will just say, tommy, I have been driving for nine years. I can't come close to managing all of these variables in the simulator, even let alone. I mean, the most I can handle when I'm driving is driving and talking and maybe adjusting brake bias here and there, but I'm just so beyond my capacity to do anymore. So how do these guys do so much? And I think more importantly for those of us who can't, what do we need to do to get better at that capacity? Or is it just so sport specific? And because these guys have been driving carts since they were five, things that I have to think about while driving, they don't. Is that simply what it comes down to?

I honestly think that's a lot of it. Many of the things they're doing, like we talked about this idea of multitasking, being running several learned subroutines at the same time, which the human brain is very good at. That's essentially what they're doing for a lot of those functions. And if you've spent your entire life as a racing driver, which they have essentially, they've been carting since they were young kids, these guys. Then when the computer setup changes or there are new things on the car based on new regulations, they're just stripping off a top layer and adding on a new one. So what they have to learn is very minimal compared to everything else that's probably happening automatically. So, yes. I mean, there's a huge cognitive demand and probably a lot of what they're actually using their brain power for in the moment is reacting to others. Right. You can't learn that.

Yeah, it's racecraft.

Yeah, exactly. And so that's where most of their attention is. And everything else is happening automatically.

Now, when you have drivers that move up the ranks and there's a pretty big jump from F3 to F2 from a complexity of the car standpoint. And again, from F2 to F1, are there things that coaches will do with the drivers during those big transition years to really help them get up to speed? I'll give you an example. And I don't think this is an example of what I'm accomplishing, but just people are probably very familiar with watching the drivers before races play sort of half physical, half cognitive games. Right. Where they have, like little lights on a board and they have to touch them or they're playing catch or juggling or doing all these sorts. Are those things doing anything to sharpen their brain or do they just look cool?

Probably a bit of both. But I would Argue that for some drivers it certainly seems to be beneficial and it's very different from driver to driver. However, there are definitely drivers who, when they move up the ranks, or even those who have been in Formula one for a long time, they'll have a dummy steering wheel, right? So they can move through the patterns of doing everything even if they're not on track. And this is often the same as when we're learning subroutines. So say you're learning a new dance, you'll do the steps one by one without music, then you'll start to string them together, then you'll add complexity and it's the same thing. So there are multiple opportunities for them to practice some of these skills, even though they don't get a huge amount of time actually racing on the track. When you're thinking about the sort of reaction games that some drivers doing, and some of them may do it in terms of practicing starts, and again, they'll have sort of a dummy setup to do that, or balls and reacting to somebody throwing something, some of it may be placebo, right? It helps them feel like they're getting ready, which is great. And anything you can do to improve that, you would welcome. But then the other part of it may be moving you onto the appropriate part of the Yerkes Dodson arousal curve, which basically says that there's this U shape or inverted U shaped curve of like how aroused you are and how you perform. And that curve is different based on the sport. And so some period where you're having to focus and react but also remain relatively relaxed because that's incredibly important, right? You want to be fast off the start line. But then the first thing you have to do is get into turn one when you have eight guys around you trying to navigate at the same thing and you have to react to them. So if you were very tense, that would decrease your performance in that setting. So I think some of it is just getting you to the point where you're focused, but then also relaxed. You know, if you're doing it with some kind of skill based thing that requires you to also be relatively fluid. So it could be like catching a ball suddenly, right? You can't do that if you're very stiff and tense. So I think some of it's this balance of getting into the right mindset before you. Then you have to do something once you get into the car.

Now, most of us were never going to be professional drivers or athletes, and certainly as we're aging, the need for really complex motor skills and Cognitive skills may go down, but what is the equivalent that you think about for a person as they reach middle life and they're thinking about transitioning or what lies ahead of them as they transition into older age? In other words, what is that apex set of skills that they need to be able to have to give them the highest amount of physiologic headroom possible to avoid or minimize this age related decline? And more importantly, potentially even avoid the pathologic stuff that we haven't talked about yet, but we'll come to.

I think a lot of it again is probably quite individual. If you want to be able to perform a specific task, you want to be able to drive cars for as long as you're able, right the next four or five decades. So then you would want to push your skills as far as you can in that arena while you're able. And then you have, like you said, maybe we'll talk more about this idea of headroom. You cannot, at least not yet. We cannot completely stop the aging process, but you may be able to slow the decline and or if you increase your level of capacity, it will take longer to get to a point where function is lost, such that you can no longer engage in that activity. When you're thinking about the brain, there's a whole bunch of things related to language skills. Obviously memory is important, but how you interact with your environment and I think social interaction is critically important and something that is probably under discussed in relation to long term cognitive function. That's a critical aspect as well, particularly as people spend less time with others because of societal effects. But when you think broadly about how cognitive function declines with age, it seems to mirror very closely the amount of demand that we put on our brains and again, how society is constructed. Because cognitive function essentially increases from birth to some peak in late teens or in your early 20s, which is the period of formal education. It is your job to learn, it's your job to develop skills. That's when most sports are learned, that's when languages are learned, that's when skills are learned. And then after that you essentially spent a bunch of time doing the same thing over and over, or you become hyper specialized in one specific skill and that's rewarded in a number of jobs, right? And so say you're a surgeon, you want a lot of those processes to be automatic. You don't want to have to think about all of them continuously. So it's beneficial, it makes you better at your job, but there's much less room for that period of skill Building or putting in effort into developing or providing those kinds of stimuli that then drive plastic reorganization in the brain and may increase headroom. So I think some of that natural decline with aging is a function of how we use our brains in general, in society. And then there's a drop off when we retire. And we can see that in various different types of data sets where those who retire earlier seem to experience cognitive decline sooner. And that's probably because the cognitive demand that we do get in our daily lives, the majority of that comes from work. So an important answer, I think, is if you're trying to maintain a basic set of cognitive functions, is to actively work on ways to increase headroom, increase absolute capacity throughout the lifespan. Because, I mean, at some point capacity will decrease, but you want to push that out as far as you can. Hopefully you'll die of something else before you lose the majority of your cognitive capacities.

Yeah, I mean, again, I think everybody's aware of the anecdote, right? Where, boy, Sally was just sharp as a tack and then she retired, and all of a sudden it all went to hell in a handbasket. But you hear this so many times that you realize there must be something to this. It can't just be an observational phenomenon that's best explained by something else. There may be other contributors to it. Maybe people who are retiring younger also have more health challenges. Maybe they're of lower socioeconomic. I mean, you could come up with a lot of confounders that could explain this. But I suspect that there is also a signal there. There's some fire in the presence of that smoke that says if you retire, and in its place add nothing cognitively, you could expect to see a decline. I also can't help but wonder how much of this has to do with sense of purpose, which again, I think maybe falls outside of. We're getting really warm and fuzzy outside of the scientific discussion. But the question I always have is, look, retirement should be thought of maybe as a financial decision. Maybe retiring means I no longer need to work for money, but I'm going to work on something else. And if that something else is not as cognitively demanding. Right. Let's say you go from being an accountant where, you know, it's pretty cognitively demanding. You're. You're in a spreadsheet all day and you say, well, look, I'm 65, I'm done with that, and I don't need to work anymore, but now I'm going to go and do something philanthropic where I'm going to work for. I'm really interested in homelessness as an example. I'm going to go and do X, Y and Z. You probably have more sense of purpose. You might derive more satisfaction from that, even though it's not as cognitively challenging. Do we have any sense of how that factors into it, or is that just so far outside of our ability to kind of understand risk?

The majority of studies that have looked at this, I guess they fall into two camps which partially answer your question, but don't necessarily answer it fully. The first is looking at the removal of that stimulus through retirement. It's been done in several population based studies. They usually account for medical conditions that might cause you to retire early because that's an important confounder. And when you look at other studies, there's evidence to suggest that late in life cognitive activity, so whether you regularly play chess or you dance or you do something else that's cognitive stimulating, that's protective against incident dementia or cognitive decline. So the two parts of that would say that removal of work as a major cognitive stimulus increases risk, but that adding some other kind of cognitive stimulus mitigates that risk. And there are several studies where you do some kind of cognitive training, maybe it's computer based brain training. In older adults in their 70s, you can see significant improvements in cognitive function. And if you think about all the things that are most protective in terms of preventing cognitive decline, there was a big meta analysis done by Jun Tai Yu, who's a professor in Shanghai, looking at all the different potentially modifiable factors for cognitive decline. The two most important protective ones were early in life education, which I think of as increasing headroom. So the more you learn and skills you develop early in life, and the longer you do that for the greater headroom you have, and then late in life cognitive activity, which then provides that protective factor. So I think there's enough evidence, as much as we can right now, and most of this is observational, although there are some interventional trials in older adults. You can say that if you're no longer working, if you replace it with cognitively stimulating activities, you're probably mitigating all of that risk, or at least most of it.

And we've discussed this a little bit in the podcast in the past, that not all cognitive tasks are created equal. So, you know, for example, my reading of the literature was there wasn't any evidence that doing crossword puzzles is necessarily going to do anything for you other than make you better at doing crossword puzzles. But dancing, now that's a bit different, actually, because no two steps are ever exactly the same. You're always sort of problem solving, especially if it's sort of complicated dance. Solving a business problem is more elaborate than doing Sudoku or whatever it's called, where it's, you know, they're just sort of little predictable word games. And so would you agree that maybe what you replace it with, there's also some variability in the complexity of that. And the less color by numbers or paint by numbers it is, the more likely it is to. Well, let's use that example. Painting by numbers versus painting. You're both painting, but in one case, it's a much higher level of cognitive load.

Yeah. And I think there are two streams of evidence that maybe support this. So one is around cognitive activities performed on a computer. So there are a number of different ways to do online brain training. There's a system called BrainHQ, which probably has the best evidence to support it, was actually developed by one of the researchers who sort of did a whole bunch of the primary basic research in terms of how we learn in the first place. Back in the 90s. They have some nice data that shows that if you do these complex training games, which are often reacting to something or shifting focus. Right. They require you to be. They're very interactive. Then you can see parallel improvements in things like verbal memory and executive functions. So things that you actually care about in real life, you're not just getting better at the game, you're getting better at certain cognitive functions, which is what you really care about.

And that program is called what?

BrainHQ.

And that's something that people would do online. That's like a game you would play online?

Yeah, it's a subscription service. I have no relationship with it. But in terms of online brain training systems, it's been used in a bunch of clinical studies. It's probably the best evidenced one in terms of creating sort of translational improvements in function. And then related to that, there are also studies using video games where if you randomize people to play Solitaire vs Angry Birds vs Mario 3D, the 3D game results in better improvements in working memory. And there is some response inhibition, which is a version of executive function. So the more complex the more interactive something is seems to be, the greater the improvements in cognitive function associated with it. Then related to that is work in physical activity. So you mentioned dancing. There are studies that have compared dancing to circuit training that is as cardiovascularly challenging, but obviously without that element of social interaction, music, movement, steps, reacting. And you see better improvements in the dancing group, and some people have termed this open skill versus closed skill physical activity. So closed skill is unidirectional, doing the same thing again and again. So like sitting on an exercise bike inside, you're not doing anything else at the same time, except maybe listening to a podcast versus, say, table tennis or badminton. So the physical nature of it, the cardiovascular stimulus, is the same, but you're not reacting to the environment and other people. And when you do those open skills type of physical activities, you seem to see some greater improvements in cognitive abilities. So there are those various things that say that the more domains or the more complex the interaction associated with the activity, the greater the associated improvements.

Yeah. The more variability there is. Right. To be able to walk outside on an uneven surface where the slope is constantly changing, and you kind of have to be able to physically and cognitively be aware of what's beneath your feet, gonna be a lot better for you than walking on a treadmill or even walking around a track in circles. So let's talk a little bit now about the pathology side of this thing. So again, I think listeners to this podcast have. Have a decent understanding about Alzheimer's disease and Alzheimer's pathology. We've certainly had a number of podcasts on the topic, but maybe let's just kind of refresh people's memories on the difference between Alzheimer's disease specifically, and perhaps other kinds of dementia, such as vascular dementia, frontotemporal dementia, Lewy body dementia, for that matter, and maybe even forms of dementia that don't necessarily fit neatly into these boxes.

Like you said, those are probably the four main types of dementia, although there are other ones that then are associated with maybe other neurodegenerative conditions. So the types of dementia associated with Parkinson's disease or als, they can be sort of complex and multi domain, and you might see changes in different areas of the brain. The main thing that ties together Alzheimer's disease. And this is something that's worth digging into, because I think both the genesis of the eponym as well as how we now use it is very interesting. But the thing that kind of ties together forms of Alzheimer's disease, and there are two, as we think about them, early onset Alzheimer's disease and late onset Alzheimer's disease. But what really ties them together is the neuropathology, which is if you slice somebody's brain open, particularly again within the medial temporal lobe, that's where the primary atrophy and pathology seems to exist, although it can be throughout the brain, is amyloid plaques and tau tangles, hyperphosphorylated tau within the neurons. And this was how the disease was originally classified. There was an initial case, August D. Who Alzheimer treated in an asylum for several years and then looked at her brain after she died, and he saw these things under a microscope, then collected other cases where they saw similar things. And this was done right at the beginning of biological psychiatry, where trying to find biology that explained psychiatric symptoms. And one of the things you could do at the beginning of the 20th century was look at things under a microscope after that person had died. And that's how they classified it. However, whenever you want to, we can get into how actually these pathological hallmarks correlate very poorly with somebody's symptom burden and disease progression. And the reasons why they they accumulate may be very different from person to person and may matter much less from one person to the next. However, it's these pathological hallmarks that created the classification of what we call Alzheimer's disease.

You know, it's funny, I wrote about this story in my chapter on Alzheimer's disease and pointed out that many years later they exhumed, I guess, part of her brain and lo and behold, she actually didn't have the sort of typical Alzheimer's disease that we see today, which is the disease that 99% of people with Alzheimer's disease get A very small subset. She was in that subset get a variant of the disease that is genetically predetermined. And I can't remember which one she had. I think she had PSEN1 or did she have app?

It was PSCN1, but that's actually quite hotly disputed. There was a paper in Lancet Neurology 2013 where they sequenced her brain and they supposedly found this mutation. But then another group got another sample of her brain and couldn't find any mutations associated with familial or early onset Alzheimer's disease. Though if she did have early onset, a monogenic orthosomal dominant mutation, some people have looked into her family history afterwards and her children didn't seem to get it. So even if she had a spontaneous mutation, it didn't seem to be passed on. So there are a lot of people who think that actually there's no evidence that she had a mutation.

That may be the first correction I need to make in the second edition of my book, because I noted that she in fact did have it, her PSEN one, and as a result it may be a different disease entirely. It may be that PSEN1 mutation, PSEN2 app mutations, which are all these essentially autosomal dominant deterministic mutations that result in people getting this disease and getting it very early. I mean, this is not uncommon for someone to be stricken in their 40s and certainly be dead before they're 60. What is the alternative explanation if in fact she did not have any of those mutations? What is the best case explanation for her disease, its severity, and the histologic.

Findings by some telling of the story? After examining her brain, Alzheimer was encouraged, supposedly, by his mentor, Emil Kraeplin, to gather together cases to sort of build this idea of this common pathologic process. And again, it's sort of, you know, you're recounting history, so it depends on who's telling it. But some people say that actually Alzheimer was quite reluctant to try and group these people together because they were so different. And I know you've sort of mentioned that famous line, which is that once you've seen one case of Alzheimer's, you've seen one case of Alzheimer'S, right? They're all so very different. And apparently this is something that Alzheimer felt as well. He wasn't sure that they should be grouped together. In the version of the story where she doesn't have an autosomal dominant mutation in Psem1, it's that she did have some kind of decrease in her cognitive faculties. There are a whole bunch of environmental or other factors that could play into that. We could certainly talk about that. But it led her husband to then put her into an asylum. And we know that one of the fastest ways to trigger cognitive impairment or cognitive decline is to basically remove somebody from their environment and completely remove all stimulus, social interaction and all the things that ground them in, you know, who they are. So that version of the story says that because of the asylum that she was put in and the way that she was sort of completely disconnected from her normal environment, that then triggered an acceleration in her cognitive decline, which then may be a sort of maximized version of what we might see in individuals nowadays who experience cognitive impairment and then dementia.

Do we know her APOE 4 status when they were looking for PSEN 1, did they check APOE?

That's a good question, but I don't know if they checked that or if anybody's checked, or if they have. I haven't seen it.

Let's sort of talk about the current state of affairs with Alzheimer's disease. And let's go back to a point you made earlier. Do you know what the discordance is between the presence of Amyloid beta on a histologic sample, obviously taken post mortem, and the presence of and or even severity of dementia related symptoms in that person while they were alive. And the contrapositive of that, which is to say the severity of symptoms in a person while they were alive and the absence of amyloid beta on a pathologic specimen after they've died. Because in an ideal world it would be a one to one mapping that is 100% Concordant. Anyone who has symptoms will have amyloid beta on autopsy and nobody who doesn't have symptoms will. And anybody who doesn't have symptoms never has it. And nobody who doesn't have symptoms will have amyloid. Right. It's a perfect one to one mapping. Well, it's clearly not that. So how messy is it?

It'd be nice if we could put an R squared or an R value on this to see how tightly correlated they are. I think I have to reach deep into the depths of my memory and if people have tried to do that kind of correlation, the R is somewhere around 0.1 or something, which just means.

For people it's virtually uncorrelated.

Yeah, there's a couple of percentage points maybe in the variability in cognitive function that's explained by the variability or the amount of amyloid that you have. And that's very clearly described in animal models as well as in humans. And we also. There are several studies where they've made some very good drugs that can decrease plaque burden in the brain, but that doesn't seem to then correlate with later cognitive functions and may have a high risk of side effects. Although that's a whole other story that we don't need to get into today. So pretty much anybody who dies with dementia or experiences dementia will have some burden of amyloid plaque and tau tangles. I don't think I know of a case where somebody had that without any. But we also know that these things naturally accumulate over time. And you can have people, there are multiple cases where they've looked at the pathology where you have significant burden of these neuropathological hallmarks with no decrease in cognitive function or beyond what might be expected given that person's age. And so there's a possibility that there's some other factor people are now thinking about other things that may come into play here. So microglial function, phenotype, and so microglia, the main immune cells of the brain, these are now being increasingly interrogated in Alzheimer's disease, dementia, other processes might be important. So lysosomal function is potentially important as well, which basically processes proteins for breakdown. And that gets impaired and that may trigger some of the accumulation of some of these things. But the alternative is to maybe think that some of these hallmarks may be epiphenomenal. They just accumulate in the face of neuronal stresses. And I'm speaking about this largely or pretty much only in the case of late onset Alzheimer's disease. Your brain is going to get exposed to a bunch of things, be that decreasing metabolic function, be that smoking, vascular disease. And then as neurons get stressed, they start to secrete some of these proteins or accumulate some of them. And there are some lines of evidence that suggests that some of it's actually a beneficial response. So amyloid beta has some antimicrobial and metal chelating effects. So it may be this actually a response to a stress that's then supposed to be protective. You get to a point, and they've shown this very clearly in animal models, where if you can force amyloid plaques to accumulate in large numbers, where they do start to become damaging in their own. Right, but up to that point, it may be more of an epiphenomenon or a response to a neuronal stress rather than this core sort of underlying pathological process.

Yeah, there's so much there to think about. Right. So on the one hand, you could say, well, look, is amyloid beta necessary but not sufficient for amyloid plaque? So the classic example that would be apob. APOB is necessary but not sufficient for atherosclerosis. You have to have it, but by itself it's not enough. You also have to have inflammation, endothelial damage or dysfunction for the APOB particle to get in there and cause damage. But APOB is causally related, and that's why reducing APOB reduces events. It's necessary but not sufficient. If that were true of amyloid, could it explain part of the observation that lots of people have amyloid without symptoms because it's only necessary, but by itself it's not sufficient? But that wouldn't necessarily imply causality, because it would. To have causality, you would have to say removing amyloid because it is necessary, though not sufficient, removes the disease. And as of yet, to your point, we don't really have evidence of amyloid reducing strategies working. Now, the flip side to that, which I know people will argue is it might be because those, and I don't know where I stand on this, I'm very confused by this. It might be that, well, we're applying those therapies too late and if you applied amyloid reducing therapies earlier, if we knew how to target people long before they were at the doorstop of mci, maybe we could do something about it. In this sense, it's sort of like saying, well, lowering APOB a week or a month or even a year before someone has an MI probably isn't going to help, but doing so 10 years before will. So how do you think about the causality and the necessary but not sufficient argument, and also this temporal argument of if in fact APOB is playing a role, we may be way outside of our window to do anything about it?

I'm open to that idea still, though I am sceptical. Based on the range of animal and human evidence so far, it's possible that amyloid beta is necessary. But if it is necessary, we don't have evidence that it is sufficient to cause dementing processes. There's been some recent work in this area that I feel supports the idea that maybe it may not even be necessary or sufficient, which is this process called panthos pathological anthos, which is pathological flower. This was published by Ralph Nixon's group out of NYU last year. And what they showed was that in a specific knockout model in mice, when we traditionally think about amyloid plaque accumulating, we think about it accumulating outside the neuron. And it's sort of like this whole bunch of protein that's kind of just sticking together and eventually that is injuring the neurons around it. It's being secreted, it's accumulating, aggregating, and then it's causing damage that way. What they show with some, some really nice techniques is that what's actually happening, at least in this model, is that amyloid is accumulating inside the neuron. It is aggregation inside failing lysosomes, which is supposed to process proteins, and they aggregate within the neuron, which then lyses, the cell dies, it disappears, and you leave a plaque in its place. It sort of like bursts the neuron open. And so in that setting, there's a nice quote by Nixon that says that if you're trying to remove amyloid, it's the same thing to try and treat amyloid Alzheimer's disease. It's the same thing as trying to revive somebody from the dead by removing their tombstone. That's essentially what it is. The plaque is the tombstone of a previous neuron that failed its ability to process protein and then left this in its place. There's still a lot of work to be done to say, is this what's actually happening in humans, which haven't been sort of genetically manipulated as we do with a lot of mouse models.

But that's a very stark concept, right? That's a very stark concept because it implies that ameloid is an absolute marker for something horrible. Just as walking through a town and seeing lots of tombstones tells you if they occurred over a short enough period of time, something bad happened in this town. But removing the tombstones does nothing to erase what just happened in that town. What is the critical response to their model? So the people that would be on the amyloid is at a minimum, necessary, maybe even sufficient, how would they be critical of Nixon's work?

So I think you could say that even if that's the case, even if this is not, if this is intracellular accumulation, all you've done is you've moved the site of initial accumulation. If it does hold in humans, and maybe that would be the first major criticism is show that this happens in humans. And I think that they're working on some pathological samples to see whether this is the case. You could say, well, okay, first show that this is how it works in humans. And then you could say, well, even if that's the case, all you've done is you've moved the amyloid from outside the cell to inside the cell where it first accumulates. That doesn't then stop it causing damage, being a primary causative factor. Because once that, first the neuron itself and then the structures around it could still be damaged or, you know, because then you might get microglial activation, right? You get this immune response, right? That can then trigger some of the nasty processes. So I think there's still a possibility that even if that's the process as it happens, you know, you could still say, oh, well, everything else is still the same.

So let's talk about some of the other ideas, Tommy, and we can talk about some of them broadly, But I'd like to also hear if you were Alzheimer's czar for a day and it was your job to allocate funding for both prevention and treatment, if you were going to allocate those types of dollars, presumably you'd want to have a strong sense of where to put those resources. But what are some of the other theories? Right? Sort of vascular, metabolic. Obviously there's a genetic component. So just tell me where you think it sort of shakes down, and then we can go from there as to what the implication is from where maybe we ought to be spending our resources.

We've gotten this far I've talked a lot about Alzheimer's disease. It's important for me to mention that a lot of the work and thought I've done in this arena is not on my own. I primarily have worked a lot with Dr. Josh Turknett, who is a neurologist, which I am not, and obviously has a lot of front facing experience in this. And so a lot of these ideas as they come together. We wrote a paper about the demand model. That's where some of this discussion comes from. But it's very much a collaboration with him and others. So I won't pretend that I suddenly figured anything out by myself, because I, I certainly didn't, nor can I say that I figured it out or else I'd be getting an invite from the King of Sweden sometime to go and go and meet him. But when we look at late onset Alzheimer's disease, I think we've gotten to the point where there's such a broad number of environmental and lifestyle based risk factors that seem to be critically important. That's really where I would focus my efforts. And you can definitely say that even if the brain is responding to neurological stresses or the absence of expected inputs, with the accumulation of certain pathological hallmarks, there's still some upstream process that's driving that and that's where I would want to focus. And I think our best evidence so far is in factors around diet, lifestyle and peripheral health, cardiovascular health being an important one. There was a Lancet commission report in 2020 that looked at dementia broadly and tried to estimate what amount of dementia, what proportion of dementia would be preventable. And they estimated that 40% of dementia is preventable based on population attributable risk, and a bunch of different risk factors. Looking at physical activity, body composition, diet quality, smoking, hearing loss, which I think of as a cognitive demand, which has lost educational status. And my guess is that this is actually an underestimate because they didn't include sleep, they didn't include nutrient status, particularly homocysteine status, which other individuals have suggested has a population attributable risk of around 20% for late onset Alzheimer's disease. And then they also, when you do these kind of assessments, and you've written about this recently, when you do a population attributable risk or population attributable fraction, you say if we remove this entirely, what proportion of that disease would disappear? And we have a mounting body of evidence that says that these risk factors interact. So when you do a population attributable risk, you say this is a linear effect it's additive. This. On top of this. On top of this. But in reality, we know that they're actually interactive.

Yeah, they're accretive.

So I think if you took into account other risk factors and more complex interactions between them, my guess is that the majority is probably preventable by focusing on some of those lifestyle environmental factors.

Can you say more about the homocysteine one? We definitely manage homocysteine very aggressively, so we're very liberal with our use of methylated B vitamins to keep homocysteine down. We typically target 8 or 9 as the upper limit we want to see, even though the lab reference range says up to 13 or 14 is normal. Do you have thoughts on that? And I guess also tell me about the mechanisms. Our concern is mostly through cardiovascular, by the way, because I think there we have pretty good evidence that homocysteine impairs the clearance of two molecules, SDMA and adma, that impair nitric oxide synthase, which obviously has an important role in the cardiovascular endothelial world. Perhaps it does in the brain as well. I'm just unaware.

So a lot of the work in this arena, I think we have to be indebted to somebody called David Smith, Professor David Smith, he's former chair and head of the Department of Pharmacology at the University of Oxford, who's done a huge amount of work on homocysteine and cognitive decline. And actually this dementia charity in the UK that I'm on the advisory board of, he is the chair of their scientific advisory board, he has done a number of interventional studies looking at this. The main one is the Vitacog study, where they randomized individuals with elevated homocysteine to a B vitamin supplement, it was a B12 and folic acid, and then looked at rate of cognitive decline and rate of brain atrophy. And they showed that if you could reduce homocysteine, and the greatest risk is with those with a homocysteine above 13, there's also an elevated risk in those with a homocysteine above 11. So the cutoff that I use for cognitive decline, that's based on hard evidence in the clinical literature, is 11. And you can slow cognitive decline and brain atrophy if you decrease homocysteine beyond that point. There's a number of potential reasons for this. The first is there may be a direct mechanistic effect related to the neuropathological hallmarks. So homocysteine seems to activate CDK5, which phosphorylates Tau and then also inhibit phosphatase 2a, which dephosphorylates Tau. So it may contribute to the accumulation of tau tangles, hyperphosphorylated tau in neurons, but then sort of more broadly, and where I think the majority of the action is and sort of excluding cardiovascular, is the importance of the methylation cycle in creating functional neuronal membranes. And the reason why I think this is because of evidence of how homocysteine level or B vitamin supplementation interacts with Omega 3 status. We know that if you want to try and put particularly a molecule of DHA into lipid membrane, you need to attach it or you need to create a phospholipid and that process of creating phosphatidylcholine, say which then attaches to your DHA so it can sit in your membrane. It's very methyl intensive. Right. So it requires. There are several methylation steps that require that to happen. When you look at, there are actually sub analyses of several randomized clinical trials that show. So in the Vitagog study, what they showed was that the rate of brain atrophy was only slowed in those who had in the highest tertial of omega 3 status. There was a study in the Netherlands, the B proof study, where they also showed that the benefit was greatest in those who had the highest levels of DHA. And then there's also the OmegaAD study where they supplemented with EPA and DHA, but then they saw benefit in those who had the lowest levels of homocysteine. So there seems to be an interaction between B vitamin status and Omega 3 status in terms of cognitive decline and brain atrophy. And the best way to think about that is probably both are required in order for DHA to be inserted in a functional way into a neuronal membrane.

Let's pause there for one second, Tommy, because I just want to make sure people understand what it is you're saying here, which is if you lower your homocysteine from 13 or 14 to 9 or 10, all the while maybe taking some DHA. And we haven't talked about doses, but what are we thinking? One to two grams of dha, one.

To two grams a day? Yeah.

Doing those two things together, which don't require any medical care. I mean, I've never seen a person who, with the right amount of methylfolate, methyl B12, sometimes some B6 is needed, you can pretty much always get your homocysteine into that zone coupled with a high quality dhea. No affiliation with any of these companies, but I Like Carlson's and Nordic Naturals as the two. What would you say is the risk reduction? Would you say that that's a 20% risk reduction in all cause dementia just doing something like that?

That's what others have suggested. They've calculated population attributable risks and they've. And it's actually, it's more than that.

Yeah, that was just the homocysteine.

That was just the homocysteine. Another 20% has been attributed to poor Omega 3 status.

So this is kind of frustrating because I know that there are literally hundreds of thousands of people listening to us speak right now whose homocysteine is elevated, whose DHA is low, DHEA is low. And they are unaware, and their doctors are unaware of everything you just said. And there's no drug, including a $30,000 a month drug, that is going to come close to that level of prevention. So why do you think there is such a disconnect in how we think about prevention? And we haven't even talked about the obvious stuff. Like, I'm just going to leave the obvious stuff aside. You should sleep. Sleep is important. Exercise is important. Not having type 2 diabetes is important. Controlling blood pressure is important. Not smoking is important. We're going to take those off the table. They're enormously important. But they're so obvious. We're not going to talk about them. But the homocysteine thing is not that obvious. And yet, you know, a 20% risk reduction, when you're starting with an absolute risk that's as high as AD is, that's like having a winning, a winning lottery ticket in your pocket and just not knowing it.

I can't explain why this is not better understood. Like when I've talked to physicians about this or I've, you know, I've had old age psychiatrists who are like, I'm immediately going to start measuring homocysteine and supplementing B vitamins, you know, plus or minus omega 3s. And I know David Smith a little, particularly through my work, sort of through this charity. And I think he's gotten to the point where he's incredibly frustrated. I don't want to speak for him, but basically this pretty significant body of randomized clinical trials showing these improved outcomes has not been incorporated into prevention guidelines. It's not been incorporated into things like the Lancet Commission report which looked at population attributable risk. But based on the information we have, and this is cheap, easy to do, it's easy to measure homocysteine, it's easy to measure an omega 3 index if you need to, or assess the DHA intake in your diet. I think there's, I can't say for certain, but I think there's massive potential benefit, you know, even if it's not 40% with the combination. Right, huge potential benefit here again with high quality evidence to support it.

Do you think there's just a bias in the medical community against non pharmacologic interventions? And I mean, look, there are few people that are going to stand here and be more critical of the supplement industry than I am. I really think it is a filthy industry, especially in the United States. I think it's disgusting everywhere. But in this country it's especially disgusting. And, and the total lack of regulation, the complete predatory nature of it and the total lack of quality control means that on average it's filthy. However, that doesn't mean every supplement is a bad idea. And I probably take a dozen supplements a day or you know, at least nine or ten if I were to really sit there and tally them up, including obviously methylfolate, methyl B12, B6, EPA and DHA. So right off the bat there's five. So probably take another five. But I can't help but think that there's a, there's a systemic bias in the medical community against supplements. And some of that I think is probably well founded because I know how frustrated, if I'm just going to be completely honest I get when patients show up in the practice and they have a list of 40 supplements. And I can tell just looking at them because I've done this exercise a thousand times, that 37 of them are garbage, but three of them are worth it. And I don't know what the answer is. I don't, I don't know what it takes to bridge that gap. But I guess this is just an example of where you might just have to bypass your doctor and sort of say, look, I need to know what my homocysteine level is. I need to know what my EPA DHA levels are and I can fix this on my, on my own. And by the way, since I'm in the process of telling people what supplements I like, especially given that I have no affiliation, I'm very happy to do this. So I prefer the Jaro supplement for methylfolate and methyl B12. I just find Jaro to be a very high quality supplement in general. I'm sure there are many others out there. I also like the pure encapsulations B6, so those are kind of the variants I'm using. Do you have any supplements that you've tested or found to be particularly trustworthy as far as manufacturers go?

For A lot of the supplements that I take, I like Thorne just because I know they have a. A high. A very stringent regulatory process and there's multiple points in the process where they test for impurities or contaminants. They also have a subset. So say if I'm working with a tested athlete that, you know, if you recommend a supplement, it has to be NSF for Sport certified or similar. So, you know, there's no band products in there and they have a line like that. Pure encapsulations, I think is good, momentous. Do some good supplements. I think part of the problem here is that, I mean, it depends on the medical system that you're working in, right? If you're in the uk, you're in a nationalised healthcare system. If you're over here in the us, obviously could be several different types of system. You need to be able to prescribe it, so that needs to be built into a system. And so in the uk, you can prescribe things like vitamin D. In the.

Uk, you need to have a physician prescribe those supplements to you.

No, but if you're a doctor and you want your patient to take it, then it's very hard. There's a big gray area where you then start recommending your patient go to the pharmacy to buy a supplement. I think part of it is this gray area, whereas you're protected if it's. In some respects, if it's. There's this indication that the National Institutes of Clinical Excellence. Nice. Have said this indication you can prescribe it or, you know, it's available. Right. There's kind of guidelines around it. And so I think that's missing. That's part of it. But even other physicians. So I work with a bunch of physicians who are interested in lifestyle medicine. In lifestyle medicine. I don't want to tar multiple people with the same. Everybody with the same brush, but they're very against supplements. They're like, lifestyle medicine doesn't include supplements. We don't do that. And anybody who does recommend supplements is sort of not allowed in the club, which is hugely problematic because, again, you have good evidence to say that there's benefit there. So. So some of it may be regulatory or the system and how you can get your patient these things, or whether you'll get in trouble if you start getting homocysteine tests on everybody, which they can be tricky to do. They have to be processed quickly. It's a slightly more expensive blood test compared to some other blood tests. And then there's also the. Like you said, I think there's some bias in there in terms of whether people think supplements are allowed or not.

It's really frustrating. All right, let's move on from the topic that is disappointing to me, which is one, having a winning lottery ticket in your pocket and not playing it, and two, being such a puritan in one's view that you wouldn't think everything is on the table. Right. I mean, my view is, look, Alzheimer's disease and dementia in general, very, very complicated, formidable opponent. Ideally have as many things as possible in your quiver. You should have a jab, you should have a right cross, you should have a left hook, you should have an uppercut, you should have all of the above to somehow suggest we only want lifestyle or we only want supplements or we only want drugs. I've never understood that rationale, but you're right, it permeates into cardiovascular medicine, it permeates into cancer, it permeates into everything. And it's just created a bunch of silos of people who each have probably some truth and some expertise, but are equally limited by their blind spots. So let's go back to the pathology again, just really quickly, what is sort of your unifying theory on these things? So whether it is the, the homocysteine, the limitation of omega 3 marine based fatty acids. We didn't even get into glucose hypometabolism, but it's something we've discussed a lot on the podcast. I think people are very familiar with hypometabolism. Whether we talk about low grade ischemia and the vascular microvascular disease. Do you think it's all working its way through a final common pathway of neuronal damage which leaves the tombstone in its wake. And that's the only thing that's basically common to them is that they leave the same tombstone.

Yes, that essentially summarizes my current thought process. And so again working with others I think, including David Smith, Josh Turkner, Jin Tai Yu, I mentioned earlier he did this big meta analysis on modifiable factors, risk factors for cognitive decline and trying to build this systems approach to cognitive decline or late onset Alzheimer's disease. And so then my current thought process is that all of these things are necessary. Healthy vascular supply, some kind of metabolic substrate that is taken up and available to neurons in the brain, that you have the nutrients required to build quality structure, that you have the absence of things that may impair some repair process. You mentioned a bunch of them which are clear risk factors like smoking. And then to kind of tie everything together, you require demand on the system that drives, creates a stimulus for adaptation. Those things are required in order to respond to that stimulus. And then you have a period of recovery and adaptation that allows for consolidation and plasticity. And any individual may have an issue in one or more of those areas. But then what ties them together is the tombstone that they leave in their wake. But the exact way that that looks, the exact number of tombstones, say, or how those tombstones look, or, you know, what else is going on, is probably an expression of things like genetics and other factors, which then explain some of that variability. But that's kind of. Yes, it's maybe the final common pathway, but everything that's important is happening upstream of that.

Before we leave dementia, I'd like to talk a little bit about one of the strongest associations I've ever seen with mitigating risk, which is strength. So this is often demonstrated with simple, measurable things like grip strength. But I don't think it's that the strength of your grip and the ability to open a jar is particularly important. It's just that very high levels of grip strength, very low levels of grip strength variability here is a great proxy for overall strength. People with a very strong grip, they're able to carry really heavy things, and that requires strength all the way up and down their chain. Why do you think strength has such an important bearing on both the avoidance of dementia, so from an incident standpoint, and also survivability. So just to give people some numbers, when you compare the top 10% or so of people from a strength perspective to the bottom 10%, it's about a 77,0% reduction in both incidence and mortality associated with all cause dementia. When you start to think of things that we have some control over, this also rises to the top of the list. I'm not suggesting that someone at the bottom can be at the top within a year, but if you think about this over the course of your life, this is something we can all aspire to. What do you think, from a physiologic standpoint explains such a stark relationship?

So my experience of talking about muscle mass and muscle strength with hard outcomes, say dementia or cause mortality, usually the response is, all right, calm down, bro. Clearly you like to lift weights, and therefore you think that that's the answer to everything, and people who are healthier are stronger. And that's just the confounding factor. But I think we have good evidence that that's not the case. The main one being that you can take individuals in their 70s, you can put them on a very basic resistance training program and you can see improvements both in white matter connectivity. You can do an MRI scan or you can test them on various tests of cognitive function, and you see improvements as a result of this training program. So then if you want to think about potential reasons why, the simplest is that some kind of novel movement is a direct neuromuscular stimulus. You are stimulating the brain to create new connections driving plasticity, because the recruiting of motor fibers, that that motor skill is in itself a stimulus, a cognitive stimulus. But then we also know that the muscle that you have and the amount that you move it, it's an important glucose sink. So if you think about blood sugar regulation, and we know that prediabetes and type 2 diabetes, like you said, are significant risk factors for cognitive decline and dementia. So it may be you're increasing glucose flux that helps regulate blood sugar. We also, you know, if you're moving your muscles, there's this still exploding area looking at myokines, so things released by muscle tissue that may Support Brain Function, IGF1, VEGF, BDNF, Brain Derived Neurotrophic factor that may support neuronal function, be sort of survival factors to keep neurons around. We know that exercise is also through a hormetic process, anti inflammatory, so chronic inflammatory conditions we kind of mentioned earlier, but can be associated with increased risk of dementia and you're decreasing systemic inflammation through physical activity. So that kind of group of things, I think all of those are playing a role. I don't know exactly which is most important, if any. Frankly, I'm not sure I really care that much because I know that it's a very important intervention. So and again, it's documented that it can actually work and you can implement it pretty much at any stage. So one of the reasons why it is so beneficial is because it has these multiple pleiotropic effects and they're probably at least additive, if not synergistic, as well as, yes, there will be a certain amount which says that the healthy you are, the stronger you are. So there's a little bit of that, but then there's a whole bunch of things on top of that.

When I met with similar resistance, no pun intended, to the idea of the importance of strength and muscle mass, I usually respond with something which is, look, even if strength training, meaning have a high degree of strength and muscle mass and cardiorespiratory Fitness, Even if all of those things didn't add a single day to your life, in fact, even if they shortened your life by six months, they would still more than be worth it in terms of the quality of your life, especially in that final decade, which is something that most people unfortunately don't want to pay attention to until they're in that marginal decade, as I call it. And you realize that at that point, having poor movement, being in pain, having low strength, limits your capacity for doing just about everything that people would find pleasure in, whether it be playing with their kids or simply going for a walk, or carrying out any basic activity of daily living at the extreme level. So it's a fitting way to end our discussion on this before we transition. So the other thing I want to talk with you about, Tommy, is another area where you have a great amount of expertise, and that is around head injury. About 10 years ago, I had a friend that suffered a very significant head injury riding a bike down the street, and a jogger bolted out between some parked cars. Didn't notice him riding, and they hit head to head. The jogger got the worst of it because he was wearing a helmet, but nevertheless, they were both devastated by this. He was going about 40 km an hour. She sustained multiple fractures to her head, but he sustained a concussion that was so bad that basically he wasn't himself for about two years. He's more or less himself now. Can you explain what a concussion is?

Even this? The idea of what concussion is is quite hotly debated, but in general, you would classify a concussion as a mild traumatic brain injury. With more severe traumatic brain injuries, you might think of, like complete open skull fractures and direct penetrating trauma to the brain, things like that. So this is. The skull remains intact, but there has been some transmission of force or a wave, a blast wave, say, if it's a blast injury that's been transferred to the brain, then at some level, in order to have symptoms of a concussion, you have some kind of disturbance of neuronal function, and that can either be because of abrupt loss. So there are some significant head impacts in particular, where you can get shearing of axons, direct axonal injury of the neurons, and then that cell is essentially lost as you sort of ripped it apart. But even more milder impacts may cause disturbances that include like, a neuron firing when it shouldn't. This can then create this pattern of activation again that's not expected. Or in an area of the brain where it wouldn't normally occur in a way that it wouldn't normally occur, and then this can then cause these downstream processes within cells that can cause mitochondrial damage. Swelling. You then might see the accumulation of certain pathological proteins. So tau is just like you see in Alzheimer's dementia. It's also a response to direct neuronal injury in a concussion. I work with a neurosurgeon whose definition of concussion is any impact or force to the brain that causes the disturbance of function of one neuron. Unfortunately, that's not something that we can measure because you probably need multiple or large sections of the brain to have aberrant function for you to be able to actually measure it or detect it. But those are the various processes that are going on when you get a head impact.

So it could be as, quote, unquote, mild as just a headache for a few days following a head trauma. Or it could be, in the case of this friend of mine, for a couple of years, they had a lot of photosensitivity, they had a lot of auditory sensitivity. They had difficulty processing things. They were much more irritable. How common are those types of more severe symptoms than just a headache for a few days after a hit to the head?

So in reality, it's quite difficult to say how common things are because millions of concussions happen every year in the. In the US Alone, most of which probably go unreported. And so it's only when you see more significant symptoms or something's happened in front of a. So you're playing sport, it's happened in front of a doctor. You know, you get a formal assessment and, you know, the downstream effects are varied. Can be around verbal effects, photosensitivity, noise sensitivity, effects of memory, focus, reaction time, depending on how you're measuring things. And probably some of it is exactly which area of the brain was impacted. And then there's a systemic response aspect as well. So you can only really do this in animal studies. But part of the process of the sort of the disease process after traumatic brain injury is a systemic immune response that seems to sort of contribute to some of the symptoms. So how much of an inflammatory response you get? How much of a fever do you get? That can then cause some issues throughout the brain as well.

So what do we know about the short term management of concussion and the long term? And what is the relationship between a concussion and a traumatic brain injury, which are terms that I think people are hearing. And of course, the term TBI in the past decade is sort of more front and center for people, I suspect, in large part due to two things. Right. Probably greater Understanding of TBI occurring in the battlefield and also in at least one sport, American football, though obviously it occurs in more than that.

Yeah. So like I said, the concussion is generally considered. So all of these are TBIs, traumatic brain injuries of various severities. A concussion is sometimes also known as a mild traumatic brain injury or mtbi. And I think this is where probably most of our focus today will be on, because the more severe brain injuries. So say if you do have skull fractures or penetrating head trauma, or you have significant loss of consciousness, that requires intensive care, that requires specialist neurosurgical treatment, that's probably beyond what most people here will be thinking about. But if instead you're thinking about concussions on the sports field, or blast related or sub concussive exposures, which might happen again in sports or in the military. And there's increasing evidence that says that sub concussive impacts or blasts. So an example would be sniper fire. Right. You essentially have a mini explosion happening right next to your head several times a day if you're in the range practicing. And there's some evidence to suggest that even that over time the damage can accumulate and cause issues with cognitive function. And there you call it sub concussive because each individual one doesn't necessarily cause symptoms. But depending on how you define concussion, you may or may not get symptoms anyway. So there's kind of a gray area there. But each individual one, you wouldn't be able to detect it really. But the damage seems to accumulate over time if you have a significant head impact. So say on the sports field is probably again where people are most familiar with it. There's probably two aspects that are worth separating. So there's the formal medical process and medical assessment that you should undergo. And there were people who made in multiple sports. Now they may have some baseline cognitive testing so that when you do get concussion, they retest you, they make sure that you get closer to your previous baseline before you're allowed to play again. So things like the impact assessment is often used in sort of youth and college sports. And so there's that part. But then what I'm particularly interested in is how can we mitigate the effects of an impact initially? Like are there supplementation and other strategies that we can do to make the athlete or somebody who's at high risk of concussions more resilient to that impact? And are there other things that we can do to support recovery or minimize the effect of the impact? So with the short term post concussion management, there are two or three things that I think are particularly important. So the first is thermoregulation, which is basically managing normal body temperature. My PhD was actually looking at the effects of temperature on response to brain injury. And it's very clear that the hotter your brain gets after an injury, the worse your outcome. Pretty much any type of brain injury, stroke, traumatic brain injury, also these neonatal and pediatric brain injuries that I study. And we know that a lot of sports happen in heat stressed environments. So you're on the field, you're hot already or you're out in the sun and experimentally, if you heat that brain up first, which happens during exercise, and then you have an impact and then that brain stays hot, that seems to worsen outcomes. So getting somebody out of a heat stressed environment, cooling them down if you need to, and you can use external ways to do that, you can use things like Tylenol to help regulate body temperature. And that particularly becomes important because this, at some point, a few hours later, an inflammatory response is going to kick in. And it's very common to get fever.

How long does that power or potential of that intervention last? So if a person has a concussion, you know, at 2 o' clock on a Sunday afternoon, should they be in an environment of taking Tylenol and cooling themselves off for the rest of the day? Or is that something that would, you'd want to carry out for a couple of days and just continue round the clock Tylenol to prophylactically ward off fever?

That's a great question, and it's something that the field probably still struggles with. But a period of 24 to 72 hours after the initial injury is probably the most critical. The most important thing is preventing fever. And the reason why fever causes issues is because you increase the mismatch between metabolic rate and capacity to produce energy to match that metabolism. And so if you have mitochondrial dysfunction, you're basically increasing that gap in terms of required energy production, which then exacerbates the injury.

Any evidence for cooling, Tommy? So, for example, I mean, obviously, as you know from your work, when you're doing certain types of heart surgery, you can actually cool the patient to 19 degrees Celsius, at least back when I was training, that was the sweet spot. I don't know what the temperature is today, but if you were basically doing anything where you had to cross clamp the aorta and prevent cerebral perfusion, you would cool the patient, literally have ice around their head. The anesthesiologist would cool the patient. And obviously that was very protective. So is there any evidence that someone Sustaining a concussion should go beyond just getting out of the sun and taking Tylenol, but perhaps be laying down and be, you know, bathed or at least have their head covered in ice.

The short answer is no. There's no evidence for that. And then there's a long story to answer that question. So, in animal models, and again, this is something that I've published extensively on, hypothermia is magic for acute brain injuries, right? If you can decrease core temperature by 3 to 4 degrees Celsius for 24 hours to 72 hours after the injury, you get a significant reduction in brain injury in one specific scenario, and that's acute brain injury in babies that have some kind of issue around birth, therapeutic hypothermia. So cooling to 33.5 degrees Celsius cool temperature for three days is the standard of care. It was brought into the resuscitation guidelines in 2010.

And they do that just externally. They're not using ECMO or anything like that.

Okay, no. So some of those kids can go on ecmo, but that's because of respiratory failure. And so you can call on pump, but no, this is a just an external cooling with it with a blanket. In models of tbi, it is similarly neuroprotective in animals. Huge bodies of work say that if you create a traumatic brain injury in an animal model and then cool the animal down, they get decreased injury. Dozens of trials, billions of dollars have been spent trying to replicate this in humans, and it has not worked. And people thought the temperature wasn't right, the duration wasn't right. Obviously, in traumatic brain injury, you have a very heterogeneous population. Maybe the population wasn't right, but in reality, there's no evidence that hypothermia works for concussions or any kind of traumatic brain injury. But what does seem to work is maintaining normothermia. So basically, a core temperature at or below 36.5 degrees Celsius. Ideally, there are some people out there who will sell cool caps and things. And I think I once spoke on a podcast and said what I just said, and somebody emailed me and was like, here's my unblinded open study of my cool cap in some hockey players that shows that it improves recovery from concussion. There is no high quality evidence that these things work. So particularly because externally cooling the brain, you're probably not going to get the brain cold enough to do it. What you need to do is you would need to cool the blood going up into the brain. But in reality, I don't think there's much evidence there. So focusing on preventing fever or managing fever, I think is very beneficial. But then active cooling below that doesn't seem to add anything.

And these studies, they demonstrated they were actually cooling the neck. They were demonstrating that they were achieving a significant reduction in brain temperature.

So these external devices, like cooling the neck in individuals with concussion, that hasn't been shown to be beneficial. When they've trialled hypothermia for traumatic brain injury.

Oh, I just mean. But did they demonstrate efficacy of cooling? Not that it reduced concussion, but did they show that they can cool the brain?

No. So this is another issue is that particularly with milder external forms of cooling, how do you know the brain is actually being cooled? And so in these studies, you may see, like, particularly if they're doing external cooling on the scalp, they'll measure scalp temperature and say, well, the scalp is colder, therefore the brain is colder. That's not necessarily the case. So. So, no, there isn't documented evidence that these things can directly significantly cool brain temperature.

So there's two problems, right? One is we don't know if we're even cooling the brain in these studies. And of course, therefore, we don't know if cooling the brain would minimize or mitigate this risk. It could be the complexity of the human model. And given our surface area, you know, infants have a surface area amount that allows for easy external cooling. In fact, that's one of the challenges of taking care of pediatric patients, is they're very susceptible to insensible losses in the way that adults are not. So here you're using it to your advantage. So that's very interesting. If it doesn't work, in other words, if we could be sure that those studies are indeed cooling the brain, but it is not having an impact, what is your explanation for the discordance between that and the pediatric and animal literature?

So there are two potential things that could conceivably remain as answered questions. So, one is that the majority of cooling studies, although this has been overcome in a lot of them, but the majority of cooling studies are probably not cooling soon enough. So there's actually a very narrow window, again based on animal studies, that says in an acute brain injury, you basically need to start cooling therapy within six hours, but probably ideally within three hours of the injury. Now, if you're running a clinical trial.

That'S almost impossible, right?

It's the same as doing thrombolysis in stroke, like trying to get it as soon as possible. It's very difficult. So if you could Immediately cool. Maybe that's part of the issue. The other issue, which is potentially a little bit controversial, but I think is increasingly being appreciated in the neonatal literature, is that when they did the original cooling trials, the control group were kept at 37 degrees Celsius and had a lot of fever, so.

Oh, you mean the controls were managed with Tylenol and thermoregulation to keep them at 37?

No. So originally they would. In those original cooling trials in neonates, the control group was hot. So if you look at a baby's normal temperature after they're born, they don't immediately go to 37 degrees Celsius. They may never get there. They'll slowly warm up over a day or so. But in those trials, the control group were immediately warmed up to 37, and they also frequently had fever, and they weren't managing those fevers because that was in the era where you were worried about the kids getting cold.

You may have made the controls work off and artificially created a gap.

Exactly. So in more modern cooling trials, they do targeted temperature management in the control group. So the control group is kept at 36.5 degrees Celsius, core temperature, and then compared to that, the cooling group doesn't seem to have a benefit. So some of the effect in neonates may be due to a worsening of outcome in the control group rather than benefit in the intervention group.

Very interesting. Okay. Another topic I want to ask you about is hyperbaric oxygen. And presumably this will be in the chronic phase. Not. I mean, maybe someone's looking at this in the acute phase, but address it as you see fit. But clearly I see a lot of people talking about hyperbaric oxygen. I get asked about this all the time from patients. I'm quite ambivalent about this. So I'm. I generally think the hyperbaric oxygen industry is a racket. I think there are definitely indications for it. There are clearly places like wound healing, where I think it matters. I probably think the opportunity cost notwithstanding, it might be reasonable to consider hyperbaric oxygen for brain injury. But I haven't really found any compelling data. So it's possible I just haven't been looking hard enough. And obviously you're closer to it. So what's your state of the understanding of the. The role of that?

I think the phase is critically important, firstly, because in the acute phase of injury, there is evidence that hyperbaric oxygen can be detrimental. I know of some studies where they've tried to get hyperbaric oxygen in as early as possible after traumatic brain injury and they've had an increase in negative side effects. I don't think those studies are published yet, but I've certainly heard of that work.

So presumably just creates more reactive oxygen species in a hyperinflammatory environment.

That's exactly it. And again, so you have impaired function and then you try and shove a bunch of extra oxygen in there. You're essentially just driving oxidative stress. And I know of some people who have actually there have been significant injuries in professional sports and they've immediately gotten that person in the chamber. That is not something that I would recommend. And I don't think there's evidence to support it longer term. So in the chronic phase, I think there's a possibility of benefit. And again, there are some data out there to suggest that those after concussion or traumatic brain injury, they may see improvement after exposure to multiple rounds of hyperbaric oxygen. However, there are a couple of things that just should drive some equipoise currently. One is that most of these trials are single arm uncontrolled studies. And it's actually quite hard to create a control group in hyperbaric oxygen studies because you can tell when the chamber is being pressurized. And so to try and create a scenario where you have a sham effect that may create the same placebo is quite tricky. The second is that I read a study where they're like these people, they all improved. We did six months of hyper oxygen, they got it twice a week. And in my mind you're just invoking Voltaire who said that medicine is the art of entertaining the patient while nature cures the disease. That brain was going to get better anyway. Having said that, I think there are some early data that suggest that improved cognitive function, maybe you're restoring metabolic function within the brain, mitochondrial function, with some periods of hyperbaric oxygen. It probably takes several rounds. So a couple of months, at least 30 plus exposures seems to be required. And again, this is sort of like anecdotal. I've seen people's pilot data. This is not large randomized controlled trials or anything like that. I think there is potential benefit.

How long after you're saying anytime after 72 hours or you'd wait even longer potentially.

I'd probably wait a couple of weeks would be my guess, until we're sort of like the full initial phase of the injury has, has. Has resolved.

And you're basically saying two 60 minute sessions weekly. And they're doing this to what depth or what's the. Whatever metric of Barometric pressure?

I think generally they do. Two atmospheres, I think is generally what's.

Two atmospheres an hour at a time? Twice a week and sometimes. Yeah, well, it's certainly long enough for Voltaire to, to take over. So it's very, it's very difficult to know. What about supplements such as creatine monohydrate and our good friends the omega 3, the marine omega 3 fatty acids, DHA and EPA, do they play any role here in supplementation if a person is not using them, I. E. Adding them, or is there any benefit for using higher doses than people might use? We typically talk about using 5 grams of creatine monohydrate daily. Talked about that in the past on the podcast. Lots of benefits associated with creatine monohydrate use, both cognitively and physically. And we talked about 2 or 3, maybe even up to 4 grams of EPA, DHA having benefit. What's the evidence for their efficacy here and how do you think about dosing them?

So I think the doses are very similar, but I do think there's a strong case for benefit. There's no good study that gives a bunch of people creatine before they get traumatic brain injuries. That's one of the problems with TBIs. It's difficult to predict, therefore it's hard to do good quality prophylactic studies. But in animal models you can see that if you supplement with creatine for several days, the optimal period may be five to seven days with a loading type dose. So the equivalent of 0.2 grams per kilo, something like that, which would the 20 grams per day for a week, the equivalent in both rats and mice before a traumatic brain injury, is significantly neuroprotective. That kind of dose and time periods. So something like 20 grams a day for a week has been shown to significantly increase brain creatine levels by doing something like magnetic resonance spectroscopy. You can point an MRI scanner at the brain and you can see the levels of creatine in it at the same time. There have been some studies in high school football athletes that have looked at that same measure over a football season and seen that related to the number of impacts that the kid gets, there's a decrease in brain creatine in the dorsolateral prefrontal cortex and the primary motor cortex. So suggesting that creatine is being used up by impacts and provides this sort of short term ph and energy buffer that may be protective when, when there's.

An impact and those kids are taking 20 grams a day throughout the season or 5 grams a day.

No, these are two separate lines of evidence.

So one is that's just looking at innate or endogenous creatine. Yeah, yeah.

So they're not supplementing. It's just looking at endogenous levels of creatine that decrease throughout the season, and it's related to. To impacts. So we know that with standard dosing of creatine, we can increase our brain creatine levels. And we also know that with impacts, brain creatine seems to decrease. And one of the thought processes behind something called second impact syndrome, which is that you have a concussion, you recover okay, you seem to be doing okay. That first concussion or that first impact doesn't have a big effect, but the next one has an outsized effect.

Yeah, we saw an awful example of this in the NFL this year with the Dolphins quarterback, right?

Yeah, yeah, exactly. And one of the things that may be happening there, some people think that at least part of that is you've depleted brain creatine with that first impact, and then there's a greater effect of the second impact, and there's probably maybe multiple things that happen because brain choline also seems to decrease in a similar manner. So I think there's. There's a case to be made for prophylactic creatine in those who are at high risk. If you can estimate when you're going to be at highest risk, I may do a loading period, 20 grams for a week. So, you know, you can increase brain creatine, but then after impact, there are several studies that. And I think this is what you've talked about previously, where creatine may improve some of the problems that happen after a concussion. So creatine can offset some of the cognitive deficits caused by sleep deprivation, and sleep can be an issue with those with concussion. In multiple studies, creatine supplementation improves cognitive function. The greatest effect seems to be in those who are oldest. But if you have some deficit in cognitive function which may be related to creatine, if it's through a concussion, then supplementation may be beneficial. And finally, there's some evidence that it may help with mood. Creatine has been tested in two randomized controlled trials where they've added it on top of SSRIs in those who responded poorly or incompletely to the SSRIs and saw improvements in depression symptoms. So I think there's multiple reasons why, if you're at high risk of a TBI or you've had a tbi, it's worth thinking about creatine Supplementation and presumably.

If you have long enough time, just being on 5 grams daily will get you what the 20 gram loading dose do. Because again to your point, if you can't predict when you're going to have a TBI, you can't always be taking 20 and waiting. If you just took five every day, you'd produce similar levels within the brain. Tell me about your thoughts on EPA or DHA specifically around this.

So for relates to concussion, I think DHA is probably the more important one and it's very similar actually to some of the processes that we thought about with cognitive decline around neuronal structure and normal neuronal function. There was one nice study where they looked at supplementing with different levels of DHA again throughout a high school football season. And what they saw they supplemented with either 2, 4 or 6 grams of DHA. And actually all of those groups with no greater benefit with a higher dose saw a decrease in play related circulating neurofilament light, which is a marker of neuronal injury that you can pick up when you get a concussion. So across the season, neurofilament light tended to increase in the athletes, but that was mitigated in the DHA supplementation groups.

Is that a biomarker you see in the blood or is that something you see on. Can you tag for it on an mri?

No, it's a biomarker you see in the blood.

Interesting. Are there any other supplements that you think should be a part of the toolkit for basically anybody? I mean, here's the reality of it is we're all kind of at risk for tbi. You get into a car accident, you have a tbi, you're walking down the sidewalk and someone bumps you while they're on their little electric scooter, you can get a tbi. So it's certainly the case that different occupations, different sports, different stages of life will have a higher versus lower risk. But it's hard for me to imagine that if there's a low risk way to mitigate it, we shouldn't all be doing it. Given that none of us know when we're going to get hit by an aberrant softball or get into a car accident or fall while we're skiing or whatever it is that we do. So what would you put in the category of kind of no regret moves along with DHA and creatine, which already have so much benefit that we've discussed in other podcasts vis a vis brain health? And in the case of creatine, not just Brain health, but also muscle performance. Anything else that rises to the level of. You got to think about it.

Yeah. So assuming that other things are taken care of. So, right. You know, you're in good metabolic health because we know blood sugar regulation is going to be important and you know your homocysteine isn't 15, that's going to be important. Then the final thing that I would say goes in that list is choline as citicoline or CDP choline.

And do you get enough of that just eating eggs or things that are rich in choline?

Yeah. So if you eat a couple of eggs a day on average, some things with lecithin in phosphatidylcholine, you're probably getting enough from the diet. But post impact, I would probably take 1 to 2 grams per day. And there's some evidence that not the choline helps with very severe traumatic brain injuries, but in survivors there's some improvement in neuropsychological outcomes in those who supplement with choline. So that's another one. Those three things I think are definitely worth considering.

And tell me the format. You would supplement the choline in Sitacholine.

Cdp, choline, which is the same thing, but alpha gpc, which is the other form of choline, is much less studied in that context. So I would take cytokoline.

Okay. And again, we're presumably we're going to the same brands that we're talking about, right. Whether it be Thorne or Jarrow or Pure Encapsulations, kind of go with a super high quality brand. Even if you're going to pay a little bit more, it's a relatively small price to pay to consider the alternative. Tommy, this is super interesting. Amazingly, we have not really spent much time on F1. Maybe I'll close with one F1 related question for the casual observer of F1. Maybe someone who knows a little bit about it, but not a lot. You get to spend a lot of time on the inside of F1. What's something that you think would surprise the casual observer about the sport and maybe something about the demands of the driver? What do you think would kind of endear people to pay closer attention to F1, which is of course my secret ambition with this podcast.

So I'm not sure if this qualifies as for your last request, but the thing that surprised me the most is probably related to the first things you said, and that is how much attention is paid to the health and performance of the driver relative to the health and performance of the car. Historically in F1, the car was everything. Basically you would just bring in a driver who was good and that was it. You'd let them get on with it. And because of the amount of travel, the amount of media commitments, so I mean, they probably spend half their time with media commitments, right, Rather than working on the car or working with the engineers or in the simulator. So probably the amount of time they have to do things like that, but because of all of that, the capacity to do a bunch of things related to their health and performance is quite small. They just don't have that availability of cognitive or time resources to do it. So they'll spend a bunch of time with their coach or trainer in the gym, aerobic work, all that stuff is important. But then things on top of that, it's very variable from driver to driver how much they focus on it. And it's also variable how much they're willing or interested in focusing on that. So what was useful to me going into that world is, and I imagine you would be the same, right? You'd show up and be like, I have a list of 100 things that are going to help. Here it is. And when you work with professional or high level endurance athletes, right, solo athletes, it's all their own performance and they're usually type A's. They will do it. They will do all 100 things, no questions asked. In that setting, you have to be really certain that the thing that you're asking that driver to do is going to be beneficial. So, you know, even if you don't have hundreds of randomized control trials, you have to be. You're really working with that sort of this idea of positive asymmetry. So like very little risk, very high potential benefit, whatever it is. And you're also selecting that one thing instead of the 99 other things on your list. So it really forces you to focus on what's going to be the most impactful thing that's actually likely to be able to make it into sort of the driver's processes and have a strong feeling that that's the thing that you should really be focusing on.

Yeah, the opportunity cost is so great and there's so many other demands, as you said. I mean, understanding the balance of the car, understanding. Because I think what most people probably also don't understand that we take for granted as, as sort of Die Hards is you've got 23 races in the year. Every race the car has to be a little bit different. Every circuit is different. So a street circuit like Monaco has pretty much Nothing in common with a big track circuit like Monza and a circuit that has lots of high speed corners without many low speed corners, is totally different than the reverse. And circuits with long straightaways where you want very low drag, very different from circuits that are short and fast. And each of those changes everything about the dynamics of the car, changes everything about how temperature gets into the tires, stays in the tires, degrades track surface, all these things. So the minute they finish that race on Sunday, they've got two weeks, sometimes one week to completely change the car, to optimize it for what they think it's going to do and behave the next week. And the driver has to be ready to do that. And. Yeah, and then someone like you comes in and says, all right, we've only got this much time to get you physically ready. And of course, the jet lag demands are sort of insane, right? I mean, it's really hard to fathom how much they are crisscrossing the globe. Actually, there's a great little video I saw on Instagram that showed the flight path of the season and it did it to the awesome, like F1 theme song. It's just so perfectly done without naming any names. What intervention or advice that you've given a driver are you most proud of in terms of the impact it's had on his performance?

Something that I really enjoyed or I thought was really impactful recently was helping a driver who was focusing on time off the start line. And of course, in general, I'm not directly interacting with the driver. The driver has a coach, and a lot of the interactions is me, the coach, and tinkering with things. The coach goes away, obviously has other people they work with and kind of implement things, but there's basically various different ways to get the driver ready to react and have an optimal reaction speed off the line. But then you also want to balance that against how they might react later in the race. The arousal curve we talked about earlier, so there were various things that we tried in terms of training, reaction time. There were some supplements we tried out. So things around caffeine timing and dose tyrosine is an interesting one that may also be beneficial. I think we tinkered with that a little bit. Creatine was obviously something that came into play. There are other skills that I think translate across that kind of thing, like playing the drums. So you have to be relaxed, but you also have to be, you know, timing is critical. I don't think that one was ever implemented, but that was a thought process that we talked about there are a whole bunch of things that happened and a whole bunch of things that were changed and the outcome improved. I can't say that anything that I did made the difference, but at least we reached the end goal, which was a nice process of sort of scientifically tinkering with things to get our end goal.

Well, Tommy, thank you very much for humoring my endless fascination with F1. And thank you more than that for making time to share with me and everybody listening all of these insights. This is a fascinating discussion. I seem that the the more I learn about the brain, the less I know, which is a common refrain for anybody, I guess, who's trying to get deeper and deeper into subject matter. So anyway, thank you very much Tommy and I. I hope to see you this year at Coda.

Yeah, likewise. Thanks so much for having me. I certainly feel the same about the brain, and that's one of the reasons why I'm so fascinated with it and I really appreciate the time to talk to you and then obviously everybody for listening as well.

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