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

27:15And 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, 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?

27:51rather 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 could sort of break this out. There are probably two different types of multitasking. One is the automatic performance of learned 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 that steps you've learned interacting with a partner, listening to the music, you are tentatively multitasking, but those are all learned subroutines that are essentially happening automatically or subconsciously.

28:31What 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, you know, Like people have said 20 something seconds, right? 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 you to do.

29:04So 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 exercises, if I'm doing a steady state a Robic efficiency we call to zone two workout on a stationary bike. I can listen to a podcast in an audio book and be completely focused on it.

29:45I can still manage to be on a bike in pedal. That often 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 a 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?

30:22Yeah, 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 Hintzer, 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.

31:11It 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 nomads 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 1 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.

31:48Of 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 the 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.

32:28And the amount of things that they have control over on this computer that masks a raid 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.

33:08They're 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 break 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?

33:49Or 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 learn 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 already been casting since they were young kids, these guys, then when the computer set up 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.

34:35So 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 then 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?

35:15I'll give you an example. I don't think this is an example of what I'm accomplishing but just people aren't 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 of things. 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 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 informed me to one for a long time, they'll have a dummy steering wheel.

35:55So 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 were learning subroutine, so 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 these reaction games that some drivers are 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.

36:36Some that may be placebo, it helps them feel like they're getting ready, which is great and anything you can do to improve that, but you would welcome. But then the other part of it may be moving you onto the appropriate part of the Yerkes Dodson and a rouse or curve, right, which basically says that there's this u -shape or inverted u -shape curve of like how arouse 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.

37:16So 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. If you're doing it with some kind of skill -based thing that requires you to also be relatively fluid, so it can be like catching a ball suddenly, you can't do that if you're very stiff and tense. So I think some of it is 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, we're 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.

37:53But what is the equivalent that you think about for a person as they reach middle life and they're thinking about transitioning, you know, or what lies ahead of them as they transition into into older age? In other words, what is that apex set of skills that they need to be able to have to 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?

38:38the 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 about 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.

39:19But how you interact with your environment, and I think social interaction is critically important and something that is probably under -disgust 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 declined 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.

40:06It 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 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 there'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 and the brain, and may increase headroom.

40:53So I think some of that natural decline with aging is a function of how we use our brains in general and society. And then there's a drop off when we retire and we can see that in various different types of datasets 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.

41:34Because 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 professors. Yeah, I mean, again, I think everybody's aware of the anecdote, right? Where boy, you know, Sally was just sharp as a tack and then she retired and all of a sudden, it all went to hell on a hand basket. 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.

42:10Maybe people who are retiring younger also have more health challenges. Maybe they're of lower socioeconomic side. 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, and 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 gonna work on something else.

42:54And if that something else is not as cognitively demanding, let's say you go from being an accountant, where it's pretty cognitively demanding, 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?

43:28The 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 adventure or cognitive decline.

44:12So 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 a computer -based brain training in older adults in their, you know, sevensies. 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 metanascist done by Gentai, Yu, his professor in Shanghai, looking at all the different potentially modifiable factors for of cognitive decline.

44:56The 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 later 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 cognitive -estimulating activities, you're probably mitigating all of that risk, or at least most of it.

45:29And we've discussed this a little bit in the podcast in the past that not all cognitive tasks are created equal. So, for example, my reading of the literature 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, no, 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 Sadduco or whatever it's called, where they're just sort of little predictable word games.

46:03And 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. They'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 were a number of different ways to do online brain training. There's a system called BrainHQ, which probably has the best evidence to support.

46:45what 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'd 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, they're very interactive, then you can see parallel improvements in things like verbal memory and executive function. 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.

47:18And that program is called what? Brain HQ. 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 evidence 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 versus angry birds versus Mario 3D, the 3D game results in better improvements in working memory and there is some response and inhibition which is a version of executive function.

47:59So 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.

48:39So, like, sitting on an excise 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 skill type of physical activities, you seem to see some greater improvements in cognitive abilities. So there were those various things that say that the more domains or the more complex the interaction associated with the the activity, the greats of the associated improvements.

49:12Yeah, the more variability there is, right? It's 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 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, front or temporal dementia, Louis -Body dementia for that matter.

49:55And maybe even forms of dementia that don't necessarily fit neatly into these boxes. Like I said, those are probably the four more 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.

50:29But the thing that kind of ties together forms of Alzheimer's disease, and there were 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 neuro pathology, 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 plucks 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, out -simer, 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.

51:22And 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 some of these symptoms burden and disease progression. And the reasons why they accumulate may be very different from person to person and may matter much less from one person to the next.

52:01However, is 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 and pointed out that many years later they exhumed, I guess, part of her brain and low 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 PSCN1 or did she have APP?

52:41It was PSN1, but that's actually quite highly disputed. There was a paper in Lancet, Erology 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 early onset Alzheimer's disease. Though if she did have early onset a monogenic Alzheimer's mutation, some people have looked into her family history afterwards and her children didn't seem to get it. 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.

53:18That 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, or PSCN1, and as a result, it may be a different disease entirely. It may be that PSCN1 mutation, PSCN2, 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 struck 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?

53:59by some telling of the story after examining her brain, Alzheimer's encouraged, supposedly by his mentor, Emil Krapelin, to gather together cases to sort of build this idea of this common pathologic process. And again, it's sort of, you know, your 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.

54:36And 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 also known with dominant mutation in PSN1, 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 stimuli, social interaction, and all the things that ground them in who they are.

55:16So 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 maybe a sort of maximized version of what we might see in individuals nowadays who experience cognitive impairment and then dementia. Do we know her apoe4 status when they were looking for PSCN1? Did they check apoe? That's a good question, but I don't know if they check that or if they haven't seen it. Let's talk about the current state of affairs with Alzheimer's disease.

55:52Let's go back to a point you made earlier, do you know what the discordance is between the presence of emaloid beta on a histologic sample? I've obviously taken postmortem and the presence of and or even severity of dementia related symptoms in that person while they were alive. And the The contrapositive of that, which is to say the severity of symptoms in a person while they were alive and the absence of emaloid 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 emaloid 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 emaloid.

56:45It's a perfect one to one mapping. Well, it's clearly not that. So how messy is it? It would 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, it's 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 and cognitive function and this is explained by the variability in all the amount of amyloid that you have. And that's very clearly described in animal models as well as in humans.

57:23And 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 won't be able to get into today. So pretty much anybody who dies with dementia or experiences dimension, we'll have some burn of amyloid plaque and towel 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, you know, there are multiple cases where they've looked at the pathology where you have significant burn of these neuropathological hallmarks with no decrease in cognitive function, or beyond what might be expected given that person's age.

58:11And 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 microglial, the main immune cells of the brain, these are now being increasingly interrogated in Alzheimer's disease dementia. Other processes might be important. So Lyesia's Omal function is potentially important as well, which is 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.

58:48They just accumulate in the face of neuronal stresses. Speaking about this largely or pretty much only in the case of late on -sciumers 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 suggest that some of it's actually a beneficial response. So, Amaloid beta has some antimicrobial and metal -calating effects. So it may be this actually a response to a stress that's then supposed to be protective.

59:28You 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 emyloid beta necessary but not sufficient for emyloid plaques? So the classic example that would be APOB. APOB is necessary, but not sufficient for atherosclerosis.

1:00:03You have to have it, but by itself it's not enough. You also have to have inflammation and ethereal 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.

1:00:45And 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 emaloid 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.

1:01:26but 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'm skeptical based on the range of animal and human evidence so far. It's possible that Amoribita is necessary, but if it is necessary, we don't have evidence that it is sufficient to cause dimenting 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 pathological pathological which is pathological flower.

1:02:19This 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. Well, they show us some really nice techniques is that what's actually happening, at least in this model, is that amyloid is accumulating inside the neuron.

1:02:57It is aggregation inside failing lysisomes, which is supposed to process proteins, and they aggregate within the neuron, which then lysis the cell dies, it disappears and you leave a plaque in its place. It's sort of like burst 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 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.

1:03:39There's still a lot of work to be done to say is this was actually happening in humans, which haven't been 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 Amaloid 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?

1:04:15So the people that would be on the emaloid 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 It's interested in accumulation. All you've done is you've moved the site of initial accumulation if it does hold in humans. 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 where this is the case. You could say, well, okay, first show that this is how it works in humans. 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.

1:04:59That doesn't then stop it causing damage, being a primary cause to factor because because once that first and you're on itself, and then the structures around it could still be damaged, or because then you might get microglial activation, you get this immune response, that can then trigger some of the downstream processes. So I think there's still a possibility that even if that's the process as it happens, 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 all -time -resar for a day, and it was your job to allocate funding for both prevention and treatment.

1:05:38If you were gonna allocate those types of dollars, presumably you'd wanna 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, how some of these, it's important for me to mention that a lot of the work and thought I've done in the serenos is not on my own. You know, our primarily have worked a lot with Dr.

1:06:12Josh Turkner who is a neurologist which I am not and obviously has a lot of sort 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 it and others, so I won't pretend that. I suddenly figured anything out by myself, because I certainly didn't. Nor can I say that I figured it out where else I'd be getting an invite from the King of Sweden sometimes to go and meet him. But when we look at late -odd set 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.

1:06:54That'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.

1:07:40And they estimated that 40 % of dementia is preventable based on population attributable risk and a bunch of different risk factors. Looking at risk activity, body composition, diet quality, smoking, hearing loss, which I think of as a cognitive demand, which is 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 home -assisting status, which other individuals have suggested has a population of tributal risk of around 20 % for late onset Alzheimer's disease. And then they also, you know, when you do these kind of assessments, right, and you've written about this recently, when you do a population of tributal risk or population, a tributal fraction, you say, if we remove this entirely, what proportion of that disease would disappear.

1:08:30And we have a mounting body of evidence that says that these risk factors interact. So when you do a population of 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, they're actually interested. They're recreative. Yeah. So I think if you took into account other risk factors and more complex interactions between them, I 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.

1:09:11We 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 Homoyscistine impairs the clearance of two molecules, SDMA and ADMA, that impaired nitric oxide synthase, which obviously has an important role in the cardiovascular and ethereal world. Perhaps it doesn't 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.

1:09:51Professor David Smith, his former chair and head of the Department of Pharmacology at the University of Oxford, who's done a huge amount of work on home assisting and cognitive decline. And actually this dementia charity in the UK that I'm on the advisory board off, 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 ViterCog study where they brandemized individuals with elevated home assisting to a B -vitamin sublone, it was a B -12 and folic acid, and then looked at rate of coagative decline and rate of brain atrophy.

1:10:28And they showed that if you could reduce home assisting and the greatest risk is with those with a home assisting above 13, there's also an elevated risk in those with a home assisting 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 coagative decline and brain an 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, hyperphosphorolateate tau in neurons, but then more broadly and where I think the majority of the action is, and excluding cardiovascular, is the importance of the methylation cycle in creating functional neuronal membranes.

1:11:31And 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 a lipid membrane, you need to attach it or you need to create a phospholipid. And that process of creating phosphatodile coelene say, which then attaches to your DHA so it can sit in your membrane, it's very meat -all -intensive. 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 Vitacock 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.

1:12:19There 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 Omega -D study where they supplemented with EPA and DHA, but then they saw benefit in those who had the lowest levels of home assisting. So there seems to be an interaction between bevitamin status and omega -3 status in terms of cognitive decline and brain atrophy. And the best way to think about that is probably both 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 home assistant from 13 or 14 to 9 or 10 all the while maybe taking some DHA and we haven't talked about doses but would it be thinking one to two grams of DHA?

1:13:18One 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 methyl folate methyl B12, sometimes some B6 is needed. You can pretty much always get your home assisting into that zone, coupled with a high quality DHA, 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 of tributal risks and they, and it's actually it's more than that.

1:14:03Yeah, that was just the homocysteine. That was just the homocysteine. Another 20 % has been attributed to poor mega -three 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, DHA is low, and 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?

1:14:44We 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. and not having type two diabetes is important. Controlling blood pressure is important, not smoking is important. We're gonna take those off the table. They're enormously important, but they're so obvious we're not gonna talk about them. But the homocysteine thing is not that obvious and yet 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 lottery ticket in your pocket and just not knowing it.

1:15:15I can't explain why this is not better understood. When I've talked to physicians about this, I've had old age psychiatrists who are like, I'm immediately going to start measuring home assisting and supplementing B vitamins, plus or minus omega -3s. I know David Smith, a little, particularly through my work, sort of through this charity. I think he's gone to the point where he's incredibly frustrated. I don't want to speak for him, but it's basically this pretty significant body of randomized clinical trials showing these improved outcomes has not been incorporated into French and Gavide lines.

1:16:00It's not been incorporated into things like the Lancet Commission report which looked at population at triple risk. But based on the information we have, and this is cheap, easy to do, it's easy to measure home assistant is easiest to measure in omega -3 index if you need to or you know assess the the DHA in taking your diet. I think there's a can't say a 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 supported. Do you think there's just a bias in the medical community against non -pharmacologic interventions and I mean look there are a few people that are going to stand here and be more critical of the supplement industry than I am.

1:16:41I 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 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 at least nine or 10 if I were to really sit there in tally them up, including obviously methyl folate methyl B12 B6 EPA and DHA. So right off the bat, there's five. So probably taking other five.

1:17:23But 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 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 do this.

1:18:00to know what my home assisting level is. I need to know what my EPA, DHA levels are. And I can fix this 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 Jero supplement for methylfolate and methyl B12. I just find Jero 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?

1:18:37For a lot of the supplements that I take I like, Thorn. Just because I know they have a high, a very stringent regulatory process and there's multiple points in the process where they test from purities 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, and 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. Mementus 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?

1:19:12If you're in the UK, you're in a nationalized 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.

1:20:00But even other physicians so like I work with a bunch of physicians who are interested in lifestyle medicine. In lifestyle medicine I don't want to tell 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. 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 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 home assisting tests on everybody, which they can be tricky to do, right?

1:20:41They have to be processed quickly. It's a slightly more expensive blood test compared to some other blood tests. And then there's also, 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 take it 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.

1:21:19Ideally, 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.

1:21:55What is sort of your unifying theory on these things? So whether it is 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 in 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.

1:22:28Yes. That essentially summarizes my current full process. And So again, working with others, I think including David Smith, Josh Turkner, Jyn Tyu, I mentioned earlier, he did this big meta analysis on modifiable factors, risk factors for cognitive decline, and trying to build this like 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 of 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.

1:23:16You mentioned a bunch of them, which are a clear respect as 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 what else is going on, is probably an expression of things like genetics and other factors which they explain some of that variability.

1:24:04But 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.

1:24:38People 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 incidence 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 70%, 70 % reduction in both incidence and mortality associated with all -cause dementia. When you start to think of like things that we have some control over, this also rises to the top of the list.

1:25:18I'm not suggesting that someone at the bottom can be at the top within a year, but if 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, you know, hard outcomes, say dementia or all -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.

1:25:58But 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 test 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 motor skill is in itself a cognitive stimulus.

1:26:43But then we also know that the muscle that you have and the amount that you move it, it's an important glucose sinks, everything about blood sugar regulation. And we know that pre -dibities and type to diabetes, like you said, are significant risk factors for cognitive decline and dementia. So it may be increasing glucose flux that helps regulate blood sugar. We also, if you're moving your muscles, there's this still exploding area looking at myocons. So things release by my statisticia that may support brain function, IGF1, VGF, BDNF, brain derived neurotrophic factor that may support neuronal function be survival factors to keep neurons around.

1:27:23We know that excise is also through a whoretic process anti -inflammatory. So chronic inflammatory conditions we kind of mentioned earlier, but can be associated with increased risk of dementia and your 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, 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.

1:28:06As 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 cardiovascular 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 or carrying out any basic activity of daily living at the extreme level.

1:29:12So it's a fitting way to end our discussion on this before we transition. So the only thing I want to talk 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 kilometers 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.

1:29:56He'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 you know 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, there'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.

1:30:44And that can either be because of abrupt loss. So there are some significant head impacts in particular where you can get shearing of of axons, direct axon 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 the neuron firing when it shouldn't, this can then create this pattern of activation, again, that's not expected in an area of the brain where it would 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 my conductor damage, swelling, you then might see the accumulation of certain pathological proteins.

1:31:33So, tau is just like you see in Alzheimer's as dementia is 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 you know 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.

1:32:23How 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 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 form of assessment. And, you know, the downstream effects are varied, you know, can be around verbal effects, photosensitivity, noise sensitivity, effects of memory, focus, reaction time, you know, depending on how you're measuring things.

1:33:09And 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 disease process after traumatic brain injury is a systemic immune response that seems to 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.

1:33:52And 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 TBI's traumatic brain injuries of various severities. A concussion is sometimes also known as a mild traumatic brain injury or M -TBI. 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.

1:34:42That requires specialists and neurosurgical treatment that's there'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 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 would 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.

1:35:49So there's the formal Medical process and medical assessment that you should undergo and there will people who made you know in multiple sports now they may have some baseline cognitive testing so that when you do get a 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 the 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 of of 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 a recovery or minimize the effect of the impact?

1:36:38So with the short term post concussion management, there are two or three things that I think are particularly important. So the first is thermoregulation, and 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 in that brain stays hot, that seems to worsen outcomes.

1:37:36So 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 tire and ultra -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 two 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?

1:38:09Or is that something that would you'd want to carry out for a couple of days and just continued around the clock Tylenol to prophylactically warden the day? our 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 metabolism. So if you have my condral dysfunction, you're basically increasing that gap in terms of required energy production, which then exacerbates the injury.

1:38:51Any 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 profusion, 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?

1:39:32The sure 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. If you can decrease core temperature by 3 -4 degrees Celsius for 24 hours and 72 hours after the injury, you get a significant reduction in brain injury. In one specific scenario, in that acute brain injury, in babies that have some kind of issue around birth. Therapeutic hypothermia, so cooling to 3 .5 degrees Celsius core temperature for three days is the standard of care.

1:40:13It 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 cool on pump. But no, this is just an external cooling 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 call that 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.

1:40:50And 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 normal thermias, 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.

1:41:32There is no high quality evidence that these things work. So particularly because it's externally calling the brain, you're probably not gonna 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. So, 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.

1:42:05So 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.

1:42:42That's not necessarily the case. 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.

1:43:19So, you hear 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.

1:44:10Now, 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 call, maybe that's part of the issue. The other issue, which is potentially a little bit controversial, but I think is increasingly 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 the thermoregulation to keep them at 37?

1:44:51No. So, originally, they were 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 those seven 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 feces. Because that was in the era where you're worried about the kids getting cold. You may have made the controls worse off and artificially created a gap. Exactly.

1:45:26So 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. I mean, maybe someone's looking at this in the acute phase, but address it as you see fit.

1:46:05But 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 not with standing. 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.

1:46:39So what's your state of the understanding of the role of that? I think the phase is critically important. Firstly, because in the acute phase of injury, There was evidence that hyperbureaucroxygen can be detrimental. I know of some studies where they've tried to get hyperbureaucroxygen 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 a impaired function and then you try and shove a bunch of extraction in there, you're essentially just driving oxidative stress.

1:47:20And I know some people who have actually, you know, there have been significant injuries in like professional sports and they've immediately gotten that person on 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 was some data out there to suggest that those after concussion or traumatic brain injury, they may see improvement after exposure to multiple rounds of high parachroxygen. However, there are a couple of things that just should drive some equipoise.

1:47:51Currently, one is that most of these trials are single arm uncontrolled studies. It's actually quite hard to create a control group in high -bargox genes. Studies because you can tell when the chamber is being pressurised. So, to try and create a scenario, we 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, you know, we did six months of high -fibre oxygen, they got it twice a week. And in my mind, you're just invoking Voltae who said that medicine is the art of entertaining the patient -long nature cure's disease, right?

1:48:31That brain was gonna get better anyway. Having said that, I think there are some early data that suggest that, you know, improved cognitive function, you know, maybe you're restoring metabolic function within the brain might to conjure a function with some periods of hyperburetoxin. It probably takes several rounds, so like 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?

1:49:06I probably wait a couple of weeks, would be my guess. Until we're sort of like the full initial phase of the injury has resolved. And you're basically saying two 60 -minute sessions weekly, and they're doing this to what depth or whatever metric of barometric pressure. I think generally they do two atmospheres, I think is generally the most fun. Two atmospheres an hour at a time, twice a week, and sometimes several months. Well certainly long enough for Voltaire to take over, which is 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?

1:49:48Do 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 five 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 two or three, maybe even up to four 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 dose is very similar, but I do think there's a strong case for benefit.

1:50:27There's no good study that gives everybody, a bunch of people creating before they get traumatic brain injuries. That's one of the problems with TBI as it's typical 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, you know, 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.

1:51:00that 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 a 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 door slatural prefrontal cortex and the primary most cortex.

1:51:37So 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 there's an impact. And those kids are taking 20 grams a day throughout the season or five grams a day. No, these are two separate lines of evidence. One is that, yes. Just looking at innate or endogenous creatures. Yes, that's, 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 impacts. So we know that with standard dose of creatine, we can increase a brain -creating levels.

1:52:11And we also know that with impacts, brain -creating 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, that was 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 creating with that first impact and then there's a greater effect of the second impact.

1:52:45And there's probably maybe multiple things that happen because brain co -learn also seems to decrease in a similar manner. So I think there's a case to be made for prophylactic creating 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 can increase brain creating. But then after impact, there are several studies that, and I think this is what you've talked about previously, where that 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 concussion.

1:53:23In 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 a high risk of a TBI, or you've had a TBI as well, think you've had a creatine supplementation.

1:53:59And presumably, if you have long enough time, just being on five grams daily, we'll get you what the 20 gram loading does do. So you, because again, to your point, you can't predict when you're gonna 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 related 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 and 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 the two four or six 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.

1:54:58So across the season your effilament 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 a, can you tag for it on an MRI? No, it's a biomark 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.

1:55:33So 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.

1:56:11Anything else that rises to the level of, you got to think about it? Yeah, so assuming that other things are taking 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 home assistant isn't 15, that's going to be important. then the final thing that I would say goes in that list is colean as citticoline or cdp colean. And do you get enough of that just eating eggs or things that are rich in colean? Yeah, so if you eat a couple of eggs a day on average, some things with less of thin in, phosphatidol colean, you're probably getting enough from the diet.

1:56:47But post the impact I would probably take one to two grams per day. And there's some evidence that that not the colean helps with very severe traumatic brain injuries, but in survivors, there's some improvement in your psychological outcomes in those who supplement with colean. So that's another one. Those three things, I think, are definitely worth considering. And tell me the format you'd supplement the colean in? Citicoline slash CDP colean, which is the same thing. But alpha GPC, which is the other form of colean, is much less studied in that context. So I would take citicoline. Okay. And again, presumably we're going to the same brands that we're talking about, right?

1:57:22Whether it be Thorn or Jero 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?

1:57:58What do you think would kind of endear people to pay close attention to F1, which is of course my secret ambition with this podcast? So I'm not sure if this qualifies as 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 were just bringing 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, working with the engineers or in the simulator, where it's probably the amount of time they have to do things like that.

1:58:48But 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, of 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 gonna help.

1:59:27Here it is. And when you work with professional or high -level endurance athletes, right? Solo athletes, they're all, it's all their own performance. And they 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 the thing that you're asking that driver to do is gonna 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.

2:00:08So 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.

2:00:43So 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 Degraids tracks surface. I'll be saying 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.

2:01:39And of course the jet lag demands are sort of insane, right? I mean, it's really hard to fathom how much they are criss -crossing 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.

2:02:19And of course, in general, I'm not directly interacting with a driver. The driver has a coach and a lot of the interactions is me and the coach and thinking 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.

2:03:00Tyra Zeein is an interesting one that may also be beneficial. We think we think about that a little bit. Creatine was obviously something that came into play. There are other skills that I think translate across to 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.

2:03:35Well, 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 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 hope to see you this year at Coda. Yeah, likewise. And 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.

2:04:10And I really appreciate the time that's talked to you. And then obviously everybody for listening as well. Thanks, Tom. Thank you for listening to this week's episode of the drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in -depth, exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. Now, that end, membership benefits include a bunch of things. One, totally kick -ass comprehensive podcast show notes that detail every topic paper, person, thing we discuss on each episode.

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