A Tale of Two Studies (on brain atrophy)


Welcome to Better Brain Fitness, hosted by doctors Josh Turknet and Tommy Wood. In this podcast, we will explore the frontiers of how to keep our brain fit and healthy so that we can perform at our best and do the things we love for as long as possible. Let’s go okay welcome again to the Better Brain Fitness Podcast. I am joined, as usual, by my cohost, doctor tommy Wood hello tommy hello. So today’s episode we are going to deviate a little bit from our usual format, but it’s for a worthy cause. So we there are two recent studies that came out, both of which are relevant to our purposes here about the topic of brain health and fitness and things that lead to cognitive decline and dementia.

00:58 : Both of these happen to be kind of about brain atrophy in particular. And so that will kind of be the overarching theme here. So the first of these was an article that came out recently in the journal Neurology about the connection between brain atrophy and the anti amyloid antibody treatments that have recently emerged and Tommy’s going to kind of give us the big picture overview of this study and we’ll try to keep it at that kind of high level for this because we could dig in to a lot of these details but Tommy take it away what did that study show us? Sure so I guess just to give the context of the things we’re interested in, as we’ve talked about before, the volume of your brain, how much of your skull is filled with brain decreases with age.

01:53 : And this is something that we see in everybody on average and it sort of precedes at least this the decrease in brain volume precedes certain loss of cognitive faculties. So it’s not necessarily that you’re that neurons are dying and you’re losing neurons, although that can be part of it it’s usually because their size decreases, they’re less supported by the other cells around them there’s less of these complex structures, protein structures and the matrix that surrounds these cells that sort of isn’t maintained and because of that volume decreases but basically we know that the faster your the volume of your brain or how much of your skull is filled with brain decreases, the faster that decreases, the faster your cognitive function decreases and the greater likelihood that you will get some kind of formal dementia so that’s why we’re interested in this because it’s important like brain volume is a good, it’s just a good measure of risk of all these things.

02:53 : And so the 1st paper like Josh said published in neurology recently is called Accelerated brain Volume loss caused by anti Beta Amyloid Drugs, a systematic review and meta analysis. So the sort of the overarching idea of this paper was they looked at randomized controlled trials where some kind of anti amyloid drug was given and where they looked at longitudinal changes in brain volume and they broadly looked at two classes of drugs and when we do a meta analysis you kind of combine everything together and then you can also do the sub analysis where you look at individual components on it, on individual factors.

03:38 : And so you know, the overall message was that these drugs that decrease amyloid in the brain also seem to accelerate the loss of brain volume or you know accelerate or decreases in brain volume compared to a placebo. When they kind of dug into this a little bit further, they separated out two different, the two main classes of drugs. One is these secretase inhibitors and what they do is they basically stop your neurons from secreting or you know, creating amyloid in the 1st place.

04:18 : Those drugs in particular seem to have the largest effect on overall brain volume and then particularly affecting the hippocampus, which again we’ve talked about previously as being this area of the brain that’s critically important for memory. It’s in this part of the brain called the medial temporal lobe and there’s all these structures around there that are really important for encoding and then accessing memories. So secrete’s inhibitors specifically affected this area of the brain and they hypothesized that and as many people have said, including us, that you know what, amyloid in itself isn’t necessarily bad like it has some useful functions as a reason why your brain makes it and that’s one of those is the small amounts of amyloids seem to be neurotrophic and support the sort of encoding of memories.

05:06 : And this, you know, is sort of part of that normal process so your neurons make amyloid as they generate new connections and store memories. Then another part of it could be that amyloid is protective in some way. And we know that, you know, different aspects of amyloid can protect against infections, can chelate or protect against things like heavy metals and other exposures so there are potential benefits to amyloid and it seems that if you completely stop them being excreted at all from the cells, this seems to accelerate loss of both total brain volume as well as that the hippocampus in particular so kind of just saying that you know some amyloid at least seems to be beneficial, we can’t just get rid of it entirely, we can’t stop it being produced entirely that seems to be a bad idea.

05:55 : Then the other type of drugs that they looked at are these anti amyloid plaque antibodies that kind of go in and help the sort of like tag these plaques and then they get that get removed by the immune system. And these are some of the drugs that have been, there are a couple of them in recently approved like Adie Helm or ADA canumab and what they found was that there was a subtype of these antiamyloid antibodies that seemed to particularly increase the volume of the ventricles so they weren’t decreasing the volume of the brain, they were increasing the volume of these spaces inside the brain where CSF cerebral spinal fluid that kind of coats and surrounds the brain is flows through.

06:43 : And this is a tricky thing to think about because there are two reasons why your ventricles might get bigger, right they’re inside, They’re in the middle of the brain, and they’re filled with fluid. And they could either increase in size because the total, the volume of the brain has decreased like we were just talking about and so then there’s more space in the skull that has to be filled and it gets filled with fluid and the ventricles get bigger. Or it could be that the way that the fluid flows through the ventricles is blocked or inhibited in some way and then fluid accumulates so it’s not.

07:17 : So it’s kind of pushing from the inside out. And everything that they kind of show in this paper suggests that it’s probably more the latter because brain volume isn’t decreasing it’s just that the size of the ventricles is increasing. And they suggest that maybe these drugs are blocking like lymphatic flow like the effect they’re affecting how fluid flows through the brain. And this and the size of your ventricles similarly is also associated with risk of dementia like the faster your ventricles increase in size and then and they sort of dug into this a little bit more and it seems that in particular the types of antibodies that affect this of those that cause something called Aria which is amyloid related imaging abnormalities and this is these are these this is an imaging side effect that’s being seen in some of these drug trials.

08:12 : And there are two different types broadly there’s an edema type which basically suggests swelling of the brain and then there’s a hemorrhagic type so like small bleeds that are happening in the brain and they specifically focused on the edema type. And essentially what they found was that the more amyloid got reduced in the brain by these drugs so the greater reduction in amyloid, you can measure this on a on a imaging scan called a PET scan, so that the more plaque they removed, the more on average of these edema related Arias were seen and the more ventricles seems to enlarge.

08:53 : So there’s definitely this specific effect of these types of drugs that seems to be causing more edema in the brain. And then this seems this is somehow affecting fluid flow through the brain and as a result the ventricles are increasing in size so again just kind of suggesting that manipulating the system may be associated with accelerating either a loss of brain volume or other markers that we know are predictive of long term cognitive decline and dementia. And the overall sort of message from the paper was that on average if you give these drugs your brains, your brain will change in a way that will get you to something that looks like Alzheimer’s disease 8 months faster than if you weren’t taking this drug and this is in patients who had mild cognitive impairment so you have some impairment already.

09:44 : And in general, the imaging looks like you’re accelerating the negative changes by manipulating these systems. This podcast is brought to you by the Brain Joe Academy. The Brain Joe Academy provides brain boosting whole brain stimulation in the form of neuroscience based musical instruction designed for adult brains and with no prior musical experience required. Start your brain boosting musical journey today at Brain Joe dot Academy. So I thought this is, you know this is really interesting and certainly quite worrying it you can say for some drug types so if you have a monoclonal antibody that doesn’t cause Aria that didn’t seem to cause these changes so you know it’s it would be fair to say that it is specifically if we’re causing, you know some of these negative side effects and they can be detected.

10:44 : But what’s interesting and you know where I’ll sort of wrap up, is that the authors had to infer a lot of stuff because these data just aren’t published in the way that they should be so in the, in the prespecified analysis for the Agihelm trials, they said they were going to look at brain volume loss, but those data never appeared and nobody’s ever mentioned them and the FDA didn’t see them or at least didn’t report on them. So some of these things are kind of they should be out there, but they’re not so, you know, sometimes there wasn’t baseline data they had to kind of infer what the baseline might look like.

11:21 : So we can’t say this is definitive because they had to kind of interpolate some stuff and that really says that for whatever reason a lot of the data that we would need to really understand this just isn’t being released from the clinical trials even if they said that they would release it and you know I think we can just sort of you know we don’t want to say much more than that but you certainly it seems like this data really needs to come out so that we can better understand how these drugs are affecting the brain and that that’s one of the things they recommend including saying that if you’re a clinician and you’re and you’re prescribing these drugs, you really should be testing or looking for these negative side effects in your patients rather than just assuming they’re going to be good because they’re reducing amyloid in the brain.

12:07 : That’s great summary thank you. And it’s pretty alarming overall. I mean, you know, it’s basically causing the exact opposite effect of what we’re trying to accomplish with these drugs. Some of our listeners might recall when this, when this, the first of these was approved maybe a couple years ago now. There was a pretty significant backlash from a lot of people a lot of, they’re all just a lot of people saying, you know, a, the evidence of benefit is pretty marginal. There appears to be some very significant side effects here.

12:41 : You know, they didn’t feel like it was, you know, it merited approval and yet it was pushed through and so we, you know, we already kind of squeaked by now we’re having this sort of finding emerge which wasn’t part of the original you know, data. You know, it’s I guess it’s still conceivable there may be some subset of the of population that could be, could be helped by this, but I don’t think we know who that is yet.

13:10 : It’s hard to argue that on balance either worthwhile to be using you know at scale before we know more so I’m curious to see what the response is going to be to this particular article i think it’s pretty significant that it was published in one of the major journals. Yeah, I think that was great too. But I think the biggest key takeaway is you know if there is indeed even best case scenario, if there’s a subset of population that you know where the net benefit is, you know where there is net benefit even if it’s marginal, these aren’t going to be the cures these aren’t going to be the thing is that we’re we’ve been looking for and you know, and this is you know, frustrating in the sort of conventional research community since we’ve been sort of banking on these being the thing for, you know, a few decades now, you know, and all based on the amyloid hypothesis, which again also is quite suspect now it also brings about another sort of paradigmatic issue.

14:12 : You know it’s something fundamental to the paradigm we have now for targeting this kind of disease which is when we have. So you have the class of diseases caused by a single factor, the most prototypical example of being an infection. You know a virus or bacteria that gets into the body shouldn’t be there, right. So anything that you you’re going to give to address that you know will generally be selective, it’s going to affect that thing and not the rest of you.

14:41 : Whereas all these chronic diseases that we now face are, you know, on a continuum of from normal Physiology to abnormal Physiology, not caused by any one thing and all those things are part of our Physiology so every drug we try is going to be disruptive in some way, right it’s disrupting our normal homeostatic mechanisms. We can’t predict what that’s going to do just and so often times we don’t learn what that’s going to do until sometime after, you know, many years of experience with a particular agent. So that also, you know, it both limits how effective it can be and it raises significant risk of harm.

15:22 : So again, it’s hard to conceive of how they just pharmacologic treatments in general, can make a dent in not just Alzheimer’s but all of the whole cluster of chronic diseases. Would you agree with that, Tommy? A damning silence. Well, it actually sets up really well this second study that we’re going to talk about Now, I’ll go into that one, unless you had anything further to add on the amyloid one.

15:55 : No, no, I don’t think so there’s a lot more to be done there, certainly but there’s enough here that I’d be really surprised if there wasn’t, you know, an increase in concern even amongst those people who feel like this is going to be the answer because, you know, so far it doesn’t seem to be the case yeah in fact, the opposite yeah and I know that, you know, probably is helpful for I’m sure plenty of my colleagues were already reluctant about prescribing so that those things so having this is probably helpful to it as further justification.

16:29 : Okay so the next study that we’re going to talk about was looking at brain atrophy in two different indigenous populations in Bolivia, the first being the chimani. And I think I’m pronouncing that right after having pronounced it wrong for probably years and then the most set, and they’re both indigenous populations in Bolivia. The chimani in particular have been in the news intermittently in recent years because like so many indigenous populations that have been studied there in general and much better health than Western industrialized societies, and in particular have very low rates of the diseases that are now most common in our society in our clinics today so things like diabetes, heart disease, stroke and dementia and these are things that we might lump under the term mismatch diseases And to give a little background on that so it’s been seen time and again that societies of humans that still live largely as we did for almost all of human history as hunter gatherers that those groups have very low levels of the diseases and conditions that are in commonplace today obesity, diabetes, stroke, heart disease, cancer, dementia.

17:52 : And again not coincidentally the very things that where we’ve made very you know little to no progress in pharmacologic treatment or other therapies. It’s also been shown time and again that when those populations start to adopt modern lifestyles and become westernized, so eating industrial foods becoming more sedentary that when that happens all of these diseases start to emerge. And so that’s why we use the term mismatch diseases to describe them as they are diseases observed to occur when there is a mismatch between our present habitat and our natural one.

18:29 : So it, you know, it shouldn’t come as any surprise i think that when you take an animal out of its natural habitat, including us, that it’s more likely to get sick, less likely to thrive. And these particular conditions that we see now are kind of what happens to a human when we do that. So again, the chimani, the subject of one of the subject of the studies are one such indigenous population still living kind of a hunter gatherer lifestyle, starting to adapt, adopt some Western habits and then the most set and are another group on the same category but have become even more Westernized still not to the level of, you know, most of us, but they’re kind of in this transitional phase.

19:12 : So each of these groups kind of these two groups kind of sit in different places along that continuum. And in the study what they wanted to look at specifically was brain atrophy with age in those two populations. And as we’ve discussed, it’s normal for atrophy to occur with age or atrophy just meaning loss of brain tissue and it does correlate with cognitive decline and risk of dementia as Tom Tommy talked about. And so in the study they did CT scans of the head of the brain in eleven hundred and sixty five people who were between the ages of 40 and 94 And the main finding was that while brain size did decline with age, in both of these group groups, the amount was lowest in the chimani and higher in the most satin.

20:06 : However, in both groups the decline in brain size with age was less than what is seen in the western population populations. So that was the main finding there was a couple of other things I think, findings they’re worth pointing out. The first was that the amount of atrophy was less in those individuals with higher b m i ‘s or body mass indices, and in a western population, a higher b m i ‘s almost always a signal of obesity, right so the extra mass is coming from fat tissue in the chimane. It appeared to be almost always an indicator of more lean tissue or including muscle so only 4 % of that of the population qualifies as obese compared to what around 30 % or more in western society so in this indication, higher BMI it, you know, likely reflected more muscle mass which correlated with less atrophy.

21:05 : The second notable finding was that the atrophy was also less and those who had higher non HDL cholesterol and that’s the cholesterol that we typically label as quote bad, supposedly increasing the risk of heart disease and stroke. And in this particular case, we see that higher rates of that bad cholesterol were actually associated with larger brain volumes with age. And we’ve already known that this population has exceedingly low rates of cardiovascular disease and dementia, as low as any population has been studied. And so we can’t, well we can’t conclude that, you know, elevated non HDL cholesterol protects against brain atrophy. These findings are really incompatible with the idea that it’s the cause of heart disease.

21:56 : So to reiterate the main finding, the chimane were shown to have less brain atrophy with age than western populations and the most set and had more than the chimane but less than modern humans quote modern. So supporting again this idea that the further you deviate from your natural habitat as a human, the greater the mismatch, the worse that is for the health of your brain. And I think there are a few other takeaways from this that I think are important. One is that again emphasizes the fact that lifestyle is the driving factor.

22:30 : You know, we’re apt to think of atrophy with age and a lot of things that would typically occur with age as being from, quote, aging or an aging process that is kind of inevitable and unmodifiable. But again, this shows that these differences in atrophy are being counted for by differences in lifestyle and number two. We already knew that rates of dementia and mild cognitive impairment were as low in this population as any that was has ever been studied so and 0 cases of people with dementia under the age of 80, which is pretty incredible and this study kind of indicates the same is true, is likely true of age-related cognitive decline given that it’s tightly coupled with atrophy, which I think puts kind of all of these conditions under the umbrella of mismatch.

23:25 : Next takeaway is that context is everything and we cannot interpret health markers in isolation. Their impact is always contingent upon everything else that’s happening in the body. You know the example here of elevated non HDO cholesterol in the context of a typical high sugar western diet, you know high non HDO cholesterol is likely problematic. In the context of the diet and lifestyle of the Jumani, it isn’t harmful and may even be beneficial. And Speaking of diet, I did dig up another study that characterized the diet of the Chimani as I figured people might be interested in that. So they get most of their calories from wild game, fish, domesticated animals as well as starchy vegetables like plantains, rice, manioc and corn.

24:19 : So they do eat a fairly diverse amount of foods, but actually 75 % of their calories came from 9 different foods. And then the men ate 139 grams of protein a day, the women ate 119 grams, and the average weight of a man was 61 kilos. So we’re talking, you know, around a gram per pound of body weight and those numbers of protein intake for women is double what is typical in the US and for men it’s 1 and a half times what is typical in the US especially for we’re talking about older populations. And again, the most of that protein is coming from animal foods.

25:03 : Now, as I mentioned earlier, very low rates of mismatched diseases, including dementia have been identified in many different hunter gatherer populations modern day and they’ve often have very different dietary patterns. So I don’t think the message is so much about the specific things they’re eating, but rather the things that they’re not eating and the commonalities is always that they’re eating Whole Foods, things that you can kill or grow in your garden. They’re not eating industrialized foods, chiefly sugar and industrial made oils and typically very minimal amount of grain.

25:44 : So Whole Foods with plenty of proteins without toxic industrialized foods kind of characterizes, you know, the typical common pattern. And I think that, you know, we’ve talked about support if you’re eating real food, the only real macro nutrient that seems to be worth paying attention to is protein. You know, absolute amounts of carbs and fat seem to be much less important if, again, if you’re eating, you know, sticking to the foods of our ancestors. And final point, it’s not just diet.

26:19 : So the concept of mismatch applies to our entire lifestyle, not just the food we eat which is why you hear us talking so much about other things like sleep and physical activity. Stress, circadian alignment, social connection, these are all key areas of mismatch today and each of these is likely playing a role in driving mismatch diseases like dementia. And you know, back to our first study, this entire suite of mismatched diseases including dementia and Alzheimer’s exceedingly unlikely to be fixed by a drug and you know, lifestyle is most is both cause and cure here.

26:55 : And so identifying and sharing those lifestyle factors is pretty much what this whole podcast is all about. So Tommy, anything else to add to that particular trial? Yeah, this. I really liked this paper, mainly because it supports so many of my personal biases about those are always the best ones about health and the brain and various other things so I think the main thing that I’d pull out is the overall hypothesis that they have or their first hypothesis that they explored was related to energy availability and brain volume. And what they basically suggested was that in states of low energy availability, which is common in, you know in these populations, but very uncommon in Westernized societies you know, it’s very uncommon, the people that they may be nutrient deprived, but they’re generally not calorie deprived, right? But you see so in this set, in this setting, in the sort of indigenous setting, the greater the energy availability, the more total energy you have, the larger brain volume, right, You can support a larger brain, therefore your brain is larger.

28:12 : However, in sort of industrialized westernized societies, you get to a point where we have for one of the better word, energy toxicity, right. Too much we know that too much energy either circulating or in stores out of post stores is associated with negative health effects and then that can negatively affect the brain so there’s this inverted U-shaped curve of total energy availability and brain volume.

28:40 : And So what they essentially hypothesize is the up to a point where you have the maximum amount of available energy without generating energy toxicity and so the reason why they use non HDL is because in this population it’s a marker of how much energy does this person have available, right so if they’re starved and calorically restricted their non HDL cholesterol may be very low whereas if it’s you know they have good amount of circulating energy, they have enough to kind of support all normal processes then their non HDL cholesterol is going to be higher.

29:11 : And so in this setting you have higher circulating available energy and higher muscle mass in particular this is associated with sort of the optimal brain volume whereas in our kind of society we end up seeing less muscle mass for a given BMI and sort of energy we have too much circulating energy. One interesting thing about this population was is they have a very high inflammation burden because they have a bunch of infections and so actually one of the ways that they offload energy is by having their immune system continuously fighting off disease, which is something that we don’t have anymore because of modern healthcare systems and antibiotics and things like that so it’s not saying that we should go back to the days where everybody dies of infections as is common in the Chimani but it’s just interesting that they have this path through which they’re offloading excess energy because of infections and the chimani are a group where Apo E 4 is not a risk factor for dementia it May is maybe even protective in the setting of a particularly parasitic infections which are very common in this group.

30:19 : So the so the thing that I kind of took away was that and you know maybe something that is relevant to anybody listening here is not that we necessarily have to restrict our intakes where this is a big thing about into the fasting chloric restriction and preventing the disease of aging. As long as we can create sort of a good net energy balance. And one way to do that is to increase physical activity that’s obviously very common in the chimani, increase muscle mass and then just ensure that we’re not sort of tipping over into energy excess or energy toxicity which is where we see things like types of diabetes and insulin resistance.

31:02 : So almost as long as you can, you know the more energy you can take in, you know protein critically important, the more muscle mass you can sustain without going over in you know too much which would be associated with sort of gaining excess adipose tissue And you know that may be the sweet spot and i felt that was kind of what they said as well that you know in general higher muscle mass with higher energy availability but preventing energy toxicity was really where maybe the sweet spot was in terms of brain volume.

31:38 : And you know that that’s maybe something that we can apply because you know it’s very difficult to chronically restrict calories whilst maintaining a high quality diet, say getting enough protein, getting enough nutrients. Whereas instead we could increase physical activity, we can increase muscle mass and maybe that creates this sort of protective buffer and help support the brain and that’s my preferred approach so that’s why I like this. Yeah one of the thing they noted was that the they also consumed more calories than typical in you know different reasons for that fighting off infections but also increased amount of physical activity you know, they’re more muscular.

32:19 : And I think that, you know, it’s also just highlights the really what we should be focusing on is the quality of those calories, right, Not just the absolute amounts and one kind of I think, easy way to think about, you know, what’s happened in Western societies is that, you know, there we have a fixed need for certain nutrients, protein being a big one. And you know, we’re going to kind of eat the amount of food we need to meet those nutrient needs and one of the biggest difference between the kind of Whole Foods that the chimani will be eating in the stuff that’s forming the bulk of calories for humans today is that the, you know, the ratio of energy to nutrients is going way up and what we’re eating today so we’re just having to eat more calories just to meet our and if we can meet our nutrient requirements and we, as you mentioned, we now have societies where you have obesity yet malnutrition, you know, because of that very problem, you know too much.

33:12 : You have all these foods with energy and very low nutrient quality. And so, you know, if you stick to those foods, you know, the caloric amounts don’t seem to matter that much and your brain will be much better equipped to actually regulate your, you know, fat mass because it’s dealing with foods with proportions of macronutrients that it’s that it’s that’s used to regulating. Yeah, absolutely. Okay well, anything else to add, Tommy? No, I don’t think so. I hope that people enjoyed this tour through the through the lit show. Oh, actually one thing I wanted to say was that if anybody is interested in a nice summary of the ideas of environmental mismatch, I thought the introduction to the second paper was actually a really nice sort of short summary of some of those ideas.

34:04 : And this is published in a very prestigious journal, the Proceedings of the National Academy of Sciences so, you know, in a really great place, you know, they’re sort of bringing together some of these ideas that I actually really enjoyed reading because it was quite a long introduction, but really sort of set the stage very nicely so if anybody’s interested in some of those ideas, this would be a great paper to read. Yeah, agree and again, great to see all these ideas put out there and you know, hopefully an indication that it’s becoming more mainstream and that framework is being used more and more to help us understand why we’re sick.

34:41 : All right, Well, if you guys have any other questions related to the these two, these two papers or anything else on the topic of brain health and fitness, send them our way, brainjo.academy/questions is where you can go to submit them. And I think that’s it for this episode we might do an occasional dive into a notable paper as they arise again so otherwise we’ll be back to our usual format next week.