Aging, Exercise and Brain Plasticity | Basic Science World Congress Keynote Session

great Thank You Carson that's a really nice introduction thank you everyone for being here it's really a pleasure and an honor to be here speaking to you today it's such a great forum of people researchers students doing work interesting work great work on exercise in the brain and and to spend a great a great meeting for me there's many perspectives on Aging some of which are a bit more positive than others some people focus more on the experience of getting older the wisdom associated with getting older Robert Frost once wrote the afternoon knows what the morning never suspected there are however alternative views of Aging some not so so nice when I was younger I could remember anything whether it happened or not but my faculties are decaying now and soon I should be sleek and that remember any but the things that never happened it is sad to go to pieces like this but we all have to do it Mark Twain Mark Twain is in his funny humorous way points out something that is is perspective it's a view that a lot of people hold that the consequence is the cognitive and memory consequences of getting older are in some way inevitable they're they're going to happen to all of us we all have to experience this and I'd like to raise the question here as to whether it really is epital is it as as ubiquitous as some people think it is and this is an important an important question and in fact there's some reason to have some hope in fact when we look at individual variability and just individual differences in in the way that the brain ages we see quite a bit of variability so here I put up on the screen 9 brains these are 9 different individuals we look across these nine brains can we even if we don't have any expertise in this area can we pick out those that are older so you look across let's look across these three the top panel here the brain looks pretty normal kind of what you see in a textbook the ventricles are normal size everything looks pretty good so it's probably not too surprising to hear that this these three individuals their average age is 22 this group of brains these three individuals look quite a bit of different significantly more atrophy ventricles that are much larger than they are here you don't really need to be a specialist in the field to notice differences between these three brains and these three brains the average age of these three individuals is 72 however let's look down into these three brains maybe something may be a bit in the middle maybe not as tightly packed of tissue up here maybe the ventricles are a little bit larger if we're thinking linearly we might expect maybe somewhere in middle age maybe somewhere between 22 and 72 in reality these three individuals here are actually the same mean age as these three individuals here there is significant individual variability and we see this we can quantify this is just a visual illustration of the type of variability but we can quantify we can we can plot these data out and for an example if we look here at the hippocampus the hippocampus sits in the medial temporal lobe it's critically involved in memory formation if you damage the hippocampus you experience amnesia those people older people who show changes deterioration and atrophy shrinking of the hippocampus and usually certain start to experience some memory problems which leads to Alzheimer's disease or usually that form of dementia and in fact when we plot out the data we see relative stability in the sizes of this structure up until about fifty years of age and then there's gradual decline after that normal age-related decline after the age of 50 is usually somewhere between 1 and 2% per year we start looking at people with Alzheimer's disease this rate increases to somewhere between 3 & 5 percent per year so we see this decline in the size of the campus here's another region that dorsal lateral prefrontal cortex involved in a lot of higher order cognitive functions working memory your ability to selectively attend items in your environment ignore irrelevant information this area also shows significant changes in sand shrinking and atrophy with age but you notice that the the function is quite a bit different it's more of a linear function showing decline starting to show decline almost as soon as it reached reaches a point of maturation about the age of 30 and but when you look across coming back to the point about individual variability look at the variability here look at the variability here when we when we take a few people like this individual here who's about seven years of age they have the size of the prefrontal cortex equivalent to somebody much younger this person who's also about the same age of 7 years of age they have the size of the a cortex equivalent to somebody much older we see similar types of variability in the hippocampus and in other areas so we can ask the provocative question what factors explain this type of variability is this just methodological error is this just people who are genetically lucky genetically fortunate and they've been able to age more successfully and gracefully than others or have they done something throughout their lifespan that's allowed them to show less brain atrophy then there's some of their peers and this is this is really where physical activity emerges onto the scene so in the title of my presentation I use the word brain plasticity what do we mean by brain plasticity and it's a commonly used term it's a term that is flung around in academic circles but it's a very difficult term to define and in fact quite often you hear this term being used differently in different circles if you're if you're coming from a literature focused on traumatic brain injury you might be using brain plasticity differently than you are if you're coming from an animal lab and and so the term brain plasticity is very complex but in general we mean some positive generally it's used in the the connotation is generally a positive adaptation to some environmental stimulus and sometimes that can be some damage to the head or some damage to the brain tissue and and then the brain has to adapt and I usually like to think about brain plasticity in the context of silly bunny and we often years ago there used to be a thought that that the older adult brain was incapable of really being very blessed that it wasn't very plastic whose is if you damage it or if something happens it's kind of like a rock and if you damage it you chip off a piece of the rock you're not getting anything back you're not remoulding that rock into something else but we now know that that's that's really a a simplistic perspective on brain plasticity in older adulthood that being said we do know that brain is seems to be more plastic in children and as we get older the idea of brain plasticity that we can mold the brain we can shape the brain is malleable we can we can have an impression on the brain and that this changes the the capability of the brain to adapt and change like this changes throughout the lifespan and in fact there's some good evidence that children will recover more more fully and quickly than older people when there's some damage so there's some good evidence that children have more plastic brains but does that mean that older adults lose their capacity for plasticity I don't think so and in fact coming back to silly putty we all know silly putty when you crack open that freshly fresh new egg of silly putty it's a warm nice piece of silly play right it's moldable malleable you can shape it you can twist it it's a very plastic our brains when we're young are like that freshly opened a negative silly putty as we get older our brain might be like that silly putty that sits out a little too long everyone knows what I'm talking about right it's upstarts become a little bit hard less impression about less moldable less malleable but all of us know as well if you pick up that silly putty and you start to hold it you start to warm it up you start to play with it in your hands of it what happens you gain back some of that plus the plasticity you can start to use it to make an impression to mold it and and to reshape it and so the older adult brain and I think is kind of like that that that egg of silly putty that's been sitting out a little too long it's still capable of plasticity but we just have to do maybe a little bit more in order to take advantage of that plasticity so this is where physical activity really emerges on the scene and we know a lot from human neuroimaging studies the impact of physical activity on brain outcomes that being said is still a lot left to learn and so what I'm going to talk about today is what we know in general about the impact of physical activity on brain outcomes in older adults I'm not going to really talk too much about the impact in other populations and and at the end towards the end of my talk I'm going to be referring to some of the gaps in our knowledge and where we really need to focus some of our of our new research so let me start out talking about some cross-sectional associations of my cross-sectional I mean taking a single snapshot we measure somebody's physical activity whether we're doing it through self-report or objectively we may take somebody's cardiorespiratory fitness levels just take a snapshot of their fitness levels and then examine how that is correlated with different brain measures and there's many different ways of using our imaging one of the one of the benefits of neuroimaging is that in an hour one hour scan you can capture information about the morphology and volume and thickness of regions we can get information about white matter microstructure we can get information about the functioning of different regions and how different regions communicate where are functionally connected we can get information about different metabolites the concentration of different metabolites in areas so we can get a lot of information so the field of course doesn't embark right away on our CTS you want to develop and you want to show cross-sectional associations first and this is really where the field started out so this is a result published in 2014 using in 310 people using more of an objectively measure assessment of physical activity and what they found was a modest significant association between greater amounts of moderate-intensity physical activity and hippocampal volume and this association the association between moderate intensity activity and hippocampal volume significantly mediated the kemple volumes significantly mediated the association between physical activity and better memory function so this was an important study because it was one of the early ones demonstrates that objective measures of physical activity where we can where we can describe and characterize light forms of physical activity versus more moderate intensity forms of physical activity is associated with hippocampal volume there's open other studies examining measures of fitness so for an example in 2009 we published a study with 165 adults that we collected between 59 and 81 years of age they're all free of dementia during our assessments we did collected aerobic fitness then and we did an MRI and during the MRI session we were able to isolate locate the hippocampus and and segment it from the rest of the brain what we found was a very clear and striking association so people with higher fitness levels over here had larger than the Campbell volumes than they're less certain fit periods this effect is cross-sectional it's a correlation it remains significant even when statistically controlling for age sex education and into cranial volume but it's a correlation right it's correlation we cannot make any causal claims about this we cannot say that engaging in physical activity or increasing cardiorespiratory fitness levels actually modifies the size of the hippocampus we can't say that from any of the data but it is provocative it's interesting that this region just so critically involved in memory formation is linked to Alzheimer's disease deteriorates in late adulthood that higher fitness levels are associated larger volumes this effect has been replicated numerous times throughout the literature so in children nine to ten year old children higher fitness levels associated larger the camp of our game in adolescence higher fitness levels associated with larger hippocampal volumes in early stage Alzheimer's disease patients higher fitness levels associated with larger hippocampal volumes in breast cancer survivors higher fitness levels associated with larger hippocampal volumes this has been repeated over and over again now but like I said despite how provocative and interesting this association is it's an association we cannot make any causal claims about these links so the last few slides were focusing on the campus and a lot of my talk will be focused on the campus there's a lot of research focusing on the impact of physical activity and exercise on the hippocampus in humans but that being said there's many other brain areas that seem to be linked with physical activity and fitness and so here is another correlation just a cross sectional study where we measured fitness levels and then examine how Fitness was related to volume of the of the brain and we found in all of these colored areas and these areas are all predominantly in the prefrontal reach of the brain and along the medial wall all of these areas higher fitness levels were associated with greater volume of tissue in older adults these same prefrontal areas our areas that are typically deteriorating in late adulthood so like I said earlier you can use nur imaging techniques to examine a number of different parameters and aspects of brain health and function another parameter is to examine white matter white matter are are the axons containing the axons which are the tissue that allows the different brain areas to connect and communicate to one another so they're basically like the highways of the brain and when we look across to different experiments now we find that higher fitness levels are associated with greater white matter microstructure in older people in all of these colored areas in both experiments so there seems to be quite a bit of consistency over and over again in cross-sectional studies at least that these associations exist so like I said cross-sectional studies are provocative that are interesting but they have their limitations so what have the longitudinal studies shown and if we take a step back and think about the even to take a step back maybe from the neuroimaging studies themselves what's happening in terms of risk for dementia or risk for cognitive impairments well going back to the cross-sectional studies we've known from at least the mid 1970s that older adults that are more physically active tend to help perform they're less active peers on a whole variety of different cognitive tasks and this general effect has been replicated numerous times so that's from cross-sectional research longitudinal research has shown some fairly similar patterns so in this study this is a meta-analysis examining effects across numerous studies over 33,000 individuals in this study and basically what they is they measure physical activity and then they follow these people for many years and examine their rate of cognitive change their rate of cognitive decline and what this study did was they they looked across all these studies and they found that greater amounts of physical activity were associated with about a 40% reduced risk of experiencing cognitive decline in late adulthood focusing in on a few of these studies this is a paper well known paper published in 2006 looking at dementia rates and here you can see age during the study and they abruptly just divided the amount of physical activity into greater than or equal to three times per week that or less than three times per week and basically what you can see is those people who were physically active less than three times per week showed a greater more precipitous drop basically in their their being free from dementia so basically risk for dementia was increased in the low active group in this study published a 20-17 from the Framingham Heart Study here to they divided into quartiles and those individuals in the lowest quartile showed a much more accelerated rate of cognitive impairment a tennis fan so these are again provocative but again we can't make any causal claims about this just yet there have been studies longitudinally now also examining impact on brain volume and bringing different brain metrics so in this particular study we this was part of a part of the cardiovascular health study physical activity was assessed in 1989-1990 and about nine years later 300 of them came back and they were cognitively normal and and we had brain measures on them so we were able to use this physical activity measure at this time point and predict brain volume 9 years later and then four years later they were diagnosed either as cognitively normal or with nci's dementia and we're able to examine whether brain volume at this time point was also related to their diagnosis four years later and what we found was very interesting i walking greater distances walking greater amounts in 1989-1990 was associated with greater brain volume in all of these older people nine years later in all of these areas including the prefrontal cortex the temporal cortex and hippocampus I was very skeptical at this this was a self-reported measure of physical activity collected in 1989-1990 and then we're doing these brain volume measures nine years later so we started to control for a whole variety of different measures and whatever we basically put into the model here this effect remains significant so then what we did was we took some of these areas and we divided we had ninety-nine people in this study we divided the groups into poor tiles and what we found was a someone graded effective across the the lower three quartiles some effect here but then there was a jump up in each of these areas that you see here so here's the hippocampus you see a graded effect and then much a bit of a jump up so the question that you're probably asking is well how much activity is this group actually getting this Q 4 group they are getting now remember this is a self-reported walking measure they were self-reported walking about 72 blocks per week so maybe about a mile a day that's about how much that they were warned so we took this data and we examine whether it was further related to risk for cognitive impairment and in fact greater amount of tissue in these areas that were associated with greater amounts of walking were associated with a reduced risk of experiencing cognitive impairment four years later so this was important because it linked for the first time physical activity at one point gray matter volume at another point and then risk for cognitive impairment a few years later so it showed these associations but again as I keep repeating we can't make any causal claims about this so more recently a postdoc of mine examined in the same cardiovascular health study links between physical activity and cognitive impairment and serum drive levels or plasma derived levels of amyloid the amyloid being one of the putative causal pathways by which people develop Alzheimer's disease and what what we found was that physical activity was indeed associated with cognitive impairment through changes in plasma amyloid so it seems as the physical activity might be also associated with cognitive impairment through through amyloid but again this was this is a longitudinal assessment in which physical activity was not manipulated and and so we have to be careful about the types of causal conclusions that we draw from a study like this but it is again provocative and interesting Association okay so we've covered now some cross sectional studies we've covered some longitudinal studies the meat here is really in the interventions now unfortunately as is the case in many developing and budding areas there's fewer there's less data if your studies that have been done in a randomized controlled nature most the studies as I've shown you then cross-sectional and longitudinal but that being said there have been a number of interventions a number of them and more that have been going on there have been more interventions in the context of the influence of physical activity on cognitive outcomes in the context of neuroimaging measures there's there's fewer of them but let's think here let's talk a little bit about interventions so this is a famous meta-analysis conducted by my prior graduate adviser R Kramer published in 2003 it took 18 randomized clinical trials examining cognitive outcomes and they grouped the cognitive outcomes into roughly four different areas four different domains and examined whether participating or engaging in exercise was associated with improvements in any cognitive domain in all of these studies is a teen studies all of these were done and older healthy cognitively normal older individuals and what you see here is that exercise was associated with an improvement in all cognitive domains so the one point that I want you to take home from this is that there seems to be a general effect of physical activity across a number of different cognitive domains however there's also some specificity this is now being generally referred to as the selective enhancement hypothesis that that executive function seem to be enhanced more from exercise than other cognitive domains so executive functions being these higher level cognitive processes like working memory maintaining goals cognitive flexibility all of these types of inhibition and selective attention all of these are considered executive functions so this research really pointed us to another area besides the hippocampus that might be really important and influenced by physical activity brain areas supporting executive function that is the prefrontal cortex now I showed you some associations earlier that the prefrontal cortex is in fact correlated with physical activity and fitness when we look across other meta-analyses this is a meta-analysis of Alzheimer's disease patients here too we see that cognition seems to be improved even in people with Alzheimer's disease now this being said these are two meta-analysis I'm going to come back to really important point in just a little bit some meta analyses fail to find significant effects of physical activity and on cognitive outcomes why it's important point I want you to keep that in mind cuz I'm going to come back to that in a little bit so let me design let me describe to you the general design of our exercise interventions that I'm going to be showing you some data from so we bring in older relatively inactive adults in the laboratory we do a variety of baseline assess assessment so we do cardio respiratory fitness testing we put them into an arai MRI machine we do cognitive testing and we give blood on them we randomized them either to a brisk walking or stretching and Tony control condition so the similarities and differences between these two conditions is really critically important remember this is an experimental manipulation in any experimental manipulation you want to keep everything identical between the two groups except for the thing that you're trying to manipulate and so here both groups are receiving physical activity stretching and toning is a form of physical activity we're doing this in a group format both groups come into the lab in a group format they're getting the same amount of social interaction which is important because some studies have found that social interaction also has an impact even brain function so we're making equivalent the amount of social interaction they give the same amount of instruction from our health instructors and our in our exercise trainers they come into the lab for the same amount of time three days per week for thirty four thirty to forty five minutes so the main differences here are the intensity and the type of physical activity we monitor the heart rate and our peeves of these two groups this group we make sure that they're exercising at a moderate intensity level based on their heart rate stretching and toning we make sure based on their heart rate that they're exercising in the light intensity zone so the intensity and type of physical activity was really what's different between these two groups we do this for six months or one year and we bring everybody back for follow-up assessments so here we are going to examine we want to examine the effects of a randomized exercise intervention unchanging hippocampal volume I showed you all of this cross-sectional data earlier these associations those people who are higher fit show greater hippocampal volume those people are more physically active larger hippocampal volumes can modify the size of the hippocampus is this a region that that is amenable to this type of change so in this particular study we had 120 people we had this was roughly this is the age in both groups we had slightly more women in this group all of the effects are going to remain I'm going to show you remains significant even when controlling for Ana gender affects attendance was about 80% in both groups and Fitness improved in the walking exercise group over this 12 month period so the fidelity of our intervention worked out it was was high we reliably improved Fitness in the walking exercise group compared to the stretch Tony here's what happened in the brain so I'm going to show you three different areas these are all volumetric assessments the thalamus was we used as a negative control area we didn't expect anything to change in the hippocampus alamos i don't know of any study that's really focused on the thalamus in the context of exercise in rodent literature's I don't really know of any studies in humans that are really focused on the thalamus and certainly in the context of aging if you see any age-related changes in the volume of the thalamus over a one-year period you've got probably a lot to worry about so generally no one sees changes in the volume of the thalamus over one-year period and here in fact we didn't see any changes either and there is no difference as a function of group the caudate nucleus we thought there might be some signal something happening the caudate nucleus has a lot of dopaminergic innervation it's like the Parkinson's disease we know that from a lot of animal studies and some studies and Parkinson's disease patients that physical activity likely influences the integrity and function of this region but this effect was not significant so I'm not gonna make too much out of that what's really striking is what's happening here in hippocampus we see about a one-and-a-half percent decline and those people who are an instruction and toning group this amounts to the normal age-related decline in the size of the hippocampus remember I told you earlier that the hippocampus if people over the age of 50 shows somewhere between a 1 and a 2 percent decline in this region so this is consistent but what's also striking is what's happening here in the walking room this group is showing a linear increase in its size over this 12-month period this increase amounted to about a 2% increase in this walking group Mugg might sound small but 2% given about a 1 to 2 percent per year decline in the size of the campus this amounts to almost reversing the clock by about 1 to 2 it's 12 months brisk walking was capable of altering the hippocampus in this fashion it's really remarkable I think about this particular finding well there's two things at least one is that in my opinion this demonstrates a remarkable degree of plasticity in the campus in older people the brain remains amenable to change even in these older individuals that are generally experiencing atrophy and deterioration of the brain so the older adult brain retains at least some of its capacity for brain plasticity a second important part of this is that I don't know of any pharmaceutical intervention that's been able to demonstrate the same effect so we took this data and we asked another question we said we asked are the changes in the hippocampus the size the hippocampus where they correlated at all with changes in cardiorespiratory fitness and in fact they were so here you're seeing changes positive increases growth in the size of the hippocampus in the left hemisphere the right hemisphere and changes in vo2 max and what you see is a significant correlation in both of these hemispheres both these regions so we see plasti decisions but campus what about the rest of the brain but we can measure the rest of the brain the volume and function of the rest of brain using many other techniques we can measure cortical thickness we can measure volume in a number of different areas one way is to take brain and MRI image and strip off all of the non brain tissue and segmented parlayed it into gray matter and white matter and then we can examine on a point by point basis throughout the brain how the volume of tissue varies as a function of anything we're interested in in this case physical activity or fitness exercise anything so in a six month intervention we found changes in the prefrontal cortex along the medial wall the anterior single cortex and the gnew the court was closer than the white matter tracks one important thing here notice is that we're not seeing the entire brain just uniformly grow with engaging in physical activity it's not just this general nonspecific enlargement same way that we didn't see it really in the Claudia nucleus or the thalamus we aren't seeing it globally here we're seeing it in the prefrontal primarily in the prefrontal regions and when you start looking at the literature the two areas that seem to pop up over and over again is the prefrontal cortex in the hippocampus it's not that other areas aren't affected but at least those two areas seem to be the most consistent across the literature so I mentioned to you earlier correlations with white matter I showed you correlations between fitness greater fitness levels are associated greater white matter microstructure in older adults what about an intervention unfortunately there isn't much data on this the few studies that have been conducted even suggest that maybe white matter may not be as amenable to change or at least it doesn't change as quickly as gray matter so in this this is the results of an intervention a randomized clinical intervention we didn't see any main effects or interactions between time and group on white matter measures however when we broke apart their group we found that those people who show greater changes in fitness did indeed show greater increases in white in some white matter regions so it may be dependent on the duration of the intervention it may be dependent on the tensity of intervention it may be that white matter is the effects on white matter are a bit more protracted there's a lot of questions here we really simply just don't have having answers at this point another commonly used measure for assessing brain health is assessing resting functional connectivity so this is basically assessing how connected and how how different brain areas communicate to one another now this is just a correlation matrix essentially what it comes down to so again we aren't we aren't saying that this brain region X is directly communicating to brain region Y but we can say that they are functionally connected in the sense that they seem to be their time series and signals seem to be correlated with one another and then we can examine whether that the strength of that correlation changes across time or as a function of an exercise intervention and here are results from two of these types of studies published in 2010 there been a few others published since then and what we see is increased basically walking exercise increases connectivity between areas of the frontal cortex and the anterior cingulate the medial wall and the hippocampus here the prefrontal cortex and hippocampus so again and again whether we're looking at volume studies or whether we're looking at more of these functional MRI outcomes it seems that for whatever reason hippocampus and prefrontal cortex seem to be popping up why is an important question so and I'll come back to that question maybe at the end if I've enough time so important other another important component to these data that if you looked at the scatter plots not everybody responds in the same way we have some people who join our interventions they come they exercise they're great subjects they participate and they don't show any changes in hippocampus why is that well it's likely that there might be moderators factors that are influencing how much the brain changes in cognition changes as a result of participating in exercise and moderators to be thought of in a number of different ways so for an example let's say you go out for a run or for a brisk walk you might be gaining some cognitive or brain changes gain something from going on that brisk walk or run but if every time you go for a run you stop to have a burger and a beer any benefit that you might be getting from physical activity may be mitigated by your diet so diet might be influencing the types of benefits that we see from physical activity another possibility you go out for a run every day you're gaining the benefits your brain is seen but then you come home and you engage in some intellectually stimulating activity could this accommodation should is engaging in intellectual stimulus emulation intellectually stimulating activities is this augmenting the effects of physical activity obviously we don't live in an environment where we just do physical activity and that's it we have many different factors that are influencing and probably absolutely seen any benefits that we're getting from physical activity an example here and a good example I think is gender so many studies have been finding that an older especially in order people but across the lifespan there are benefits that seem to be greater for females so first of all interventions with more females tential larger effect sizes than stays with males females with mild cognitive impairment show greater benefits of across variety of cognitive tasks female rats shield Rader changes in capillary structure after exercise in the health and retirement study only females showed reduce suppressive systems with greater amounts of physical activity greater physical activity was associated with reduced depressive symptoms only in females this was a study out of my lab however there are some other studies showing greater benefits for mammals so fitness effects are greater on white matter lesions only in males and ethanol induced depressive symptoms were mitigated by exercise but only in males so there seems to be some gender differences there we don't know exactly why but gender certainly seems to be a potential modifier of the effects of physical activity another example might be age so here is a study that we published in 2003 we found that age was associated with greater declines in gray matter and white matter volume but that Fitness moderated in these effects of age so here we get effects of fitness but the modifier is aged and basically what we found is that the effects of fitness seemed to be greater they seemed to be having a greater effect on gray matter volume measures than in younger younger age ranges genotype is another example and my colleague Carson here has done a lot of work on on the modifying effects of apoE genotype on the benefits seen in physical activity and here's another study published from Denis head so here let me explain what you're seeing here this is mean cortical binding potential of amyloid so this is you'll want you don't want amyloid in your brain it's a marker for at least a marker for Alzheimer's disease pathology and so higher bar here is something you don't want to have these this is low amounts of people or the low amount of physical activity high amounts of physical activity low amounts high amounts separated by their their efore genotypes these people are not carrying the risk allele for cognitive impairment and this group is carrying the risk allele for cognitive impairment you see this big bar this is the bar that jumps off the screen at everyone right what does this group this group is the people that are at risk for cognitive impairment based on their gene genotype but it's the low physical activity in combination with the e for risk group that shows this greater amount of Emily this is interesting but what I actually find the most interesting about this figure is what's happening right here basically this group is showing a genetic risk for high amounts of amyloid the greater risk for Alzheimer's disease but engaging in greater amounts higher amounts of physical activity actually mitigated or trumped the effect of the polymorphism on amyloid levels this has also been found in other four other polymorphisms so in a study that we published in 2013 a gene called the brain derived neurotrophic factor gene BDNF and codes for a protein called BDNF it's known to be linked with cognitive function but here too we found that the effect of the polymorphism a cognitive function was only apparent in those people getting low amounts of physical activity once we started looking at people getting high amounts of physical activity there is no effect of the polymorphism on any measure of cognitive performance so moderation here's the challenge that we face most of these studies on moderators have been done in cross-sectional studies these studies that I just show you were cross-sectional in nature part of the problem that we have is that generally you need larger sample sizes in order to really test for interactions and so most RCTs just don't simply don't have the sample size to really reliably test for these possible moderators there might be other moderators so for an example there we showed in 2007 that maybe hormone therapy use is playing a role omega-3 intake we could think about baseline fitness or physical activity levels duration or intensity of activity intellectual stimulation as I mentioned earlier and so on so up to now we've been talking really a bit more about the phenomenology of the effects and what I mean by that is we're describing the effects we haven't I haven't mentioned yet anything about possible pathways or mechanisms how people try to assess this have people tried to assess whether these volumetric changes are just meaningless byproducts of engaging in physical activity or do they have some mechanistic role in behavioural improvements do they have some importance for things that we really care about because we don't who cares about the brain if there's no benefit to behavior now obviously we're studying the brain because I do think and I think we have all good reasons to think that the brain and brain volume is important if I took a poll in here it said if I took away half your brain would you be upset about that most of you would probably say yes right you want to keep your brain healthy you want to maintain the volume and so keeping a healthy brain is important but what are the mechanisms that we can think about mechanisms on multiple levels and this is an important an important component here that I want it I want to talk about it because usually when we talk about mechanisms we think automatically right away to molecular and cellular pathways and that's perfectly fine and and in fact we can think we can ask the questions what are the molecular and cellular changes that are taking place that influence either these structural and functional brain changes or maybe psychosocial changes like sleep patterns or anything else or changes in cognitive function so molecular and cellular changes certainly a an important factor a component in the pathway by which we want to think about physical activity and behavioral changes but we can also think about how do these structural and functional brain changes that we see in relation to physical activity how do they mediate these psychosocial and cognitive changes and similarly maybe when we think about cognitive changes in cognitive improvements resulting from physical activity maybe just maybe we are seeing improvements in cognitive function because people are sleeping better and maybe it's because people are sleeping better that people are able to think better or maybe people are approaching the world differently their effect is changed their mood is changed so they're performing these cognitive tasks differently so in that case mood or sleep or these psychosocial changes would be significant mediators for the link between physical activity and cognitive function now of course all of these are dependent on one another we wouldn't expect to see structural and functional brain changes in the absence of molecular accelerator changes of course something has to be happening on that on that fundamental level so these are not mutually exclusive and in fact exercise increases a number of cellular and molecular pathways including the number of neurons and hippocampus an important molecule called brain derived neurotrophic factor it's critically involved in learning and memory is involved in cell proliferation it's found in high concentrations in hippocampus guess what and people with Alzheimer's disease if you look at people in people with Alzheimer's disease where pathology is found no BDNF is found exercise increases beating up levels in humans going back to my prior study in 2011 those people that showed greater increases in hippocampal volume show greater increases in BDNF levels similarly functional connectivity measures changes and functional connectivity are correlated with changes in serum derived BDNF levels so and here again sorry I forgot about this one here again BDNF levels changes in BDNF levels across the course of an intervention mediated improvements in executive function so we are starting to target certain cellular and molecular pathways and changes in cognition changes in brain and and starting to understand the links between these neuroimaging measures and cognitive outcomes so limitations here most studies look at correlations and do not statistically test for mediation most have small sample sizes that limit our ability to test for mediation and this is unlikely to be driven by one primary so there's we have to be thinking broadly about cerebral vascular changes inflammation insulin pathways blood pressure etc so in conclusion we can think here coming back to a point that I made earlier how consistent are the effects this is a meta-analysis published in 2015 we found no evidence in the available data that aerobic physical activities including those that successfully improve cardio taury Fitness have any cognitive benefit cognitively healthy older adults the institute of medicine in the same year produced a document based on the literature and they said that physical activity is one of the or maybe the most promising approach that we have for improving cognitive function in older people there's a lot of discrepancy and muddiness across the literature why is that okay so let me quickly go through a few different discrepancies that seem to be plaguing literature many RCTs have small sample sizes this could lead to spurious positive findings or could be related to insufficient power if people don't have the sample sizes and we're seeing just modestly sized effects having larger sample sizes could be important variability in monitoring activity and adherence compliance supervise versus home-based you can see a lot of variability in adherence rates um down to less than 40 percent many trials do not include intend to treat protocols fail to report blinding during assessments many studies fail to report baseline physical activity levels or don't include activity levels as eligibility criteria there's variability in the duration of the intervention from 4 weeks to 18 months studies that don't take these factors into consideration could be missing a lot there's variability in the intensity of the intervention some studies fail to monitor or assess fitness or objectively monitor activity there's variability in the types of control conditions and meta-analyses often combined across all of these when in fact we have good reason to believe that stretching and toning might be different than that education and wait lists and depending on how the papers analyzed there you could get different different results lack of assessment of individual differences or moderators variability and equality of cognitive assessments that are done and so there's a lot of reasons for some discrepancies in this literature and meta-analyses sometimes combine different types of physical activity interventions that are likely influencing the brain in different ways so there's many unanswered questions how long do these effects persist this is probably a very important question that all of you are asking sure all of these effects happen but we stopped exercising for a lot of different reasons how long do these effects persist we really don't have the answer what types of exercise are most effective the mode of exercise we don't know dose response effects and what are these volumetric differences reflect on a cellular level so we've we are conducting as Carson said earlier we are conducting a phase 3 clinical trial to address some of these questions and we are collecting a lot of measurements including amyloid and body composition to try to understand the effects of the dose response of physical activity on brain and cognitive outcomes in healthy older adults and also examine potential moderators genetic moderators and mechanisms so with that we've learned a lot about the impact of certain behaviors on brain outcomes and we can be pretty confident that we know that exercise and physical activity does a lot for the brain but we still have a lot to learn so coming back to the silly putty the brain still retains its capacity for some plasticity even when it's gone so exercise has widespread effects on the brain moderate intensity exercise several days a week is sufficient for improving brain health starting to exercise in late life it's not futile even those who are sedentary and a crew function and exercise may have long-term health consequences for many different zees and conditions of the brain so in conclusion I just want to thank my team because this really takes a whole village of people to do this work all of my funding agencies and my collaborators many of which I don't have enough room to really even put on this on this slide so with that I just wanna thank you for your attention [Applause]

Channel: ACSM

Views: 2,777

Rating: 5 out of 5

Keywords: ACSM, American College of SPorts Medicine, ACSM Annual Meeting, Basic Science, World Congress on basic science, brain plasticity, again and exercise

Id: xYbYQk22d4E

Length: 55min 36sec (3336 seconds)

Published: Thu Mar 15 2018