Cognition in the Oldest Old: The 90+ Study | Claudia Kawas, M.D. | LEARNMEM2018

[Music] I'm delighted to introduce our plenary speaker this morning dr. Claudia Kalos Claudia is a geriatric neurologist and professor of Neurobiology and behavior and neurology here at UC Irvine she serves as associate director of the Institute of memory impairments and neurological disorders at UCI her work focuses on the epidemiology of Aging and dementia and particularly and understand the predictors of successful aging a topic highly relevant to all of us in this room dr. kaylis has published more than a hundred peer review manuscripts and has worked on many important longitudinal studies of Aging most notably perhaps than I need plus study which he leads here at UCI her seminal work on this under study population of the oldest old addresses a really critical gap in aging research most studies tend to stop in the 80s if not even younger and Claudia's work has taught us that really interesting nonlinear changes emerge in that 10th decade of life things that are risk factors when were middle-aged promote longevity once we reach our 80s and 90s I think my favorite of her many intriguing findings from the 90-plus data is that some so-called vices actually turn out to be good for us so we can all fake claudia for empirically demonstrating that caffeine and alcohol promote longevity so let's all be sure to raise a toast to Claudia tonight at the evening reception without further ado please join me in welcoming dr. Claudia chaos [Applause] morning everyone I can't believe you're not out on the beach doing a walk but welcome to rainy grey Southern California okay so um many of you may know who this lady is Madame Rouge on Louie cálmense she was born in Arles France and so paintbrushes to Vincent van Gogh when she was a child in fact she was on a public television show in her adult life and um she described him as dirty disgusting and she didn't think too much of his artwork but in in fact the the story I'm gonna tell you mostly about madam Cao Mei was when she was 90 because this is the talk about 90 year olds so she had a very nice apartment in Paris and she made a deal with a 47 year old man that he would pay a monthly fee and when she died the apartment would be his and if he paid ten years of monthly fees he would pay the market value for this apartment and it seemed like a pretty good deal at the time but many of you probably know that she got not only ten years but then he paid for 20 years and then he paid for 30 years and then he died and then his widow paid for several more years because Jean Louie holds the Guinness world record for longest lived human she lived to be more than 122 years old and initially when I started becoming interested in the oldest old I mean most people's questions was why and I think one of the shortest answers to that is all of us in this room have a reasonably high likelihood of reaching a hundred and beyond and all of us in this room want to do it particularly with decent memory and learning and all of us in this room probably are most afraid that that might not be the case so I thought this was very interesting quote you know more than half of all children born in 2009 in the United States are expected to reach their hundred and third birthday so throughout the world the majority of the population is going to become a centenarian or even older in the coming decades and we really didn't know anything about them because in fact we specifically exclude these individuals from a lot of our studies of Aging the NI NCDs criteria for Alzheimer's disease for example that came out in 1984 specifically said we could make the diagnosis of Alzheimer's disease if somebody was between the ages of 45 and 90 and at the time I asked Bob Katzman who was one of the authors well what's wrong with 91 why can't I say somebody who's 91 has Alzheimer's disease and it was just one of very very many times that I realized how really brilliant and insightful he was but his response then was well we just don't know so when I came to UC Irvine I kept in mind all these years that we really didn't know anything about 90 or 95 or or 100 year olds for example here is H specific incidence rates for dementia throughout the world what you see let's see if this is a planar I don't think you know what you see at the left side of the of the graph is you know the risk of dementia at age 65 70 75 and 80 is relatively low certainly under 5% per year but it's also pretty much the same and it's the same in Germany which is the purple it's the same in Brazil which is down at the bottom of the graph in light blue but as we get to age 90 you start seeing these rates diverging and they diverge to the point that some study says the risk of 95 year olds to have dementia is 30% per year that's in Munich definitely in the top purple and some places say not only is it not that but it goes down compared to H 80 and 85 for example Sal Paulo at the bottom of the graph and in between you've got all kinds of estimates and there's a tenfold difference between the risks for them suggested by some studies compared to other studies and unless you really believe that everyone in Munich Germany should really move to Brazil what's going on here so we don't even know the the risk of becoming demented at this age and we don't know what are the risk and protective factors related to longevity or dementia we don't know the types of dementia people get at this age or how to diagnose them and so because of that we started the 90-plus study now it's 8:00 in the morning and I'm very intimidated by this audience who studies much more interesting learning and memory aspects than I do so I decided Mike Vyasa actually decided then I'm going to show you a few minutes of a video clip from in this case it's going to be from the 60 minutes show in the top that they did on the 90 plus study and let lesley stahl introduce our investigations because she actually is more interesting than I am we are a nation getting older by the middle of the century the number of Americans aged 90 and above is projected to quadruple dementia including that most dreaded form Alzheimer's disease is a looming threat and a primary focus of the 90-plus study I was born in August 25th 1920 and I'm 93 plus 1918 what they have in common is that decades ago they all lived in a retirement community called leisure world 45 miles south of Los Angeles today it's still a retirement community and they're still getting the most out of life though it's no longer called leisure world it's now its own City Laguna Woods dr. claudia Tawaf spends a lot of time in Laguna Woods these days she's a neurologist and professor at nearby UC Irvine who discovered the research equivalent of gold here information gathered from thousands of leisure world residents back in 1981 with page after page of data about their diet exercise vitamins and activities six million dollars of funding from the National Institutes of Health que vas and her team set out to find out who had died when they died and to convince those who were still living in over 92 sign up now please spell world they are given an hour-long battery of cognitive and memory tests at nazca world's backwards ding el árbol w they are checked from top to bottom every six months make smile their facial muscles reflexes balancing for 5 how they how fast they can stand up and sit down and most importantly all their minds are working you know unfortunately there's no blood test there's no x-ray it's an examiner finding out that an individual has problems in two or more of the main things the brain does for them so what was it that got these people into their 90's so you've never had a stroke no well they're suppose as friends and colleagues and we have hardly anything dropped out along the way what's your secret I would fair knew well whatever you secrets are by being in the study we're gonna find a math comparing that data to how it's all turned out has yielded a slew of published findings about behaviors associated with living Lorna I really believe that when we learn things from the 90 year olds they're gonna be helping the 60 and 70 year olds not just how to become 90 year olds but how to do it with style and it's good a function as possible so as you heard valishia report study in 1981 was an investigation by the university of southern california and then at what they did was they sent 14,000 they said 18,000 questionnaires to every single person who was living in what was called leisure world at the time it's now called Laguna Woods because they seceded from leisure world they didn't like the sloth it was the title and the restrictions and besides are in California and we're always receiving there and of these eighteen thousand fourteen thousand of them came back which is also a comment on luna woods it was a primarily white cohort reflecting the population both then and now mostly female because by age 70 75 there are two women alive for every man and they this was all done during the male and then we'll follow up surveys four times over the next 20 years so the first thing we did was we now know about 14,000 people about their lifestyle we know whether or not they were taking vitamin C or E supplements we know if they were drinking alcohol or overweight we know if they were self-reporting exercise or leisure activities and what we wanted to know was were any of these things associated with living longer so Karen took a little bit of my thunder but I will say that I don't know for sure but I think that and I'm not sure if I had told niña that I wanted to do a study showing that alcohol and caffeine makes you live longer if they would have been as enthusiastic so instead I said I want to show that vitamin C or E antioxidants or other things might be associated with living longer and so we hung a whole lot of our hat in fact on the whole antioxidant notion and in fact when the dust settles people who were taking vitamin C or had diets high in vitamin C compared to people of their own age as many of you probably know anyone think this matter it didn't nor did vitamin A nor did vitamin E nor did calcium nor did soft drinks no power nothing with green tea or black tea but everything else on the list did matter and when I'm asked about changing my lifestyle because the things I learned in the study if the results have been different I would have had to make a lot of changes but this made it easier especially since our body mass index finding was that people in their 80s and 90s who were overweight actually have a reduction in mortality compared to normal weight individuals and although our study was relatively modest we showed a 3% reduction which was identical to what the CDC showed in a much much much larger study so you know I one of the things I've noticed is mother nature I think does a better job of taking care of us than we do ourselves so I think that diet is very important I just don't think that vitamin C supplements are very important or vitamin E supplements and I think that mother nature much to our distress makes us gain weight as we age and I think maybe in some ways we should think that this might be a not terrible thing and maybe even a good thing I want to qualify some of the things I'm gonna say these things are only true for the people who made it to age 90 but we didn't know even if you lived long we didn't know were you living long but with dementia and maybe some of these things even if they didn't make you live longer maybe they were useful for lowering your risk of dementia or hip fractures or other things that very important so I'm not saying these things aren't important they're just not related to longevity so what we did is we wanted to see what these people look like all of the previous work had been done through mailed surveys and self-report and so we said on January 1st 2003 if you were one of these 14 thousand people and you were still alive and over the age of 90 we wanted to see you and although these individuals lived in one community just a few miles from here actually in 1981 it took 37 states to track down the 1600 individuals that we ended up enrolling so the last year or two we've been taking volunteers who aren't from this Leisureworld cohort but all the data I'm going to show you today is from the first 1,600 that we enrolled all of them we had data from 30 or 40 years ago so here's a snapshot of what they look like at their first visit you can see now there are three women alive for every man because in every species on the planet where there is a difference in longevity by sex it is always the female that lives longer and personally I think there's a nobel prize hiding in that finding for somebody for someone to figure it out it's relatively highly educated cohort and in terms of cognition on their first visit you can see it was about a third a third a third so a third of them we deemed to have dementia a third of them we felt were normal which doesn't mean their performance was identical to a 30 year old but and a third of them were in this in-between zone where they had memory or some other kind of cognitive problems but they didn't meet criteria for dementia so we asked a lot of these and virtuals I mean truth truthfully it's been extraordinary what they've done for us first of all we see them every six months and we do all kinds of neuropsychological testing neurological examination a lot of the performance measures you saw in the video we asked them to give us their DNA we asked him to give us blood samples we asked them to stick their heads at this point now in one MRI and two PET scans and at the end of it all we asked them if they'll consider giving us the brain which I think is one of the most valuable things that we've found and I'm going to show you some of the data from our autopsy today so going back to this graph one of the first things we wanted to know is if you were one of those individuals who did not have dementia the first time we saw you what was the risk of developing dementia in your 90s and here's another place that I showed how wrong I am I actually spent most of my career really believing that the risk of dementia after age 90 probably went down not or and you can see some of the numbers here actually suggests that but if the risk goes down some suggests it might level off and some suggest that it continues to go up so the bad news is there is no question now in my mind it not only goes up it continues the perfect doubling that begins at age 65 so with every 5 years of age your risk of having dementia doubles after age 65 and that's true after age 90 you can see that from 90 to 94 were right in the middle of the pack we had more data than most of these other studies so we were able to do age specific risks so it's about 10% per year in your early 90s it doubles to 20% per year and then after age 100 it's a staggering 40% per year so the risk of dementia is extremely high unfortunately and the next thing we wanted to know is is that risk of dementia may be related to all of these things I showed you before and will make with work for that dementia was not only not related to any of the things that we had suggested looking at like antioxidants but even things that we found to be related and younger individuals didn't appear to be related than older individuals so we've spent most of my career trying to separate vascular disease from Alzheimer's disease and now that I'm getting ready to retire we seem to be trying to put them back together which is probably the right thing so the next thing we did was look at vascular risk factors and you can see that half of the population had hypertension substantial numbers of people with cardiac disease of various sorts and when we looked at these in relationship to dementia it turns out pretty much nothing was related with the exception of hypertension hypertension was protective yeah nobody found it looks like either you're not awake or that doesn't surprise you but for most of us we think hypertension is not a great thing we it is well established that midlife hypertension is a risk factor for late life dementia and the fact is that we're not the first people who have found this if you study people in their 80s and 90s you get a finding like we did so you can see here actually here's the data point so car congestive heart failure stroke valve disease diabetes all the things on the left side of the screen actually now our showing to have an increased risk of dementia when you look at incident dementia but on the far right you'll see cholesterol and hypertension both of which actually it's not just that they're not a risk factor they lower the risk of dementia compared to people who never develop hypertension in their life so it actually appears protective and we I'm not going to go into this in detail on this talk I'm not gonna talk about it much anymore but I do want to make one point really really really clear when we dissected this out this effect is coming exclusively from individuals who developed hypertension in their 80s mid to late 80s or 90s so hypertension individuals in our study who developed hypertension in their 60s or 70s actually do not have an increased or a decreased risk most of these individuals have been treated and their risk is pretty much the same as if they had never had hypertension but individuals who develop hypertension in their 80s and 90s have about a 25% reduction or more in their risk of having dementia and this has actually also been shown in several studies now because this we say in my lab age matters so whatever you hear about a risk factor or anything else and find in the room I'm always asking at what age was that was that done because we've always understood that children are different than adults at one end of development we understand that the brain works differently we understand that the abilities are different the diseases are different we have a whole school of doctors to take care of neonatal or adolescence or Pediatrics but at the other end we act like we're all bad versions of 60 year olds so age H matters and and the idea we I thought it was funny there was this week in the Saturday in the Tuesday's science sections of the New York Times there was an article sort of entitled clinical trials are happening old need not apply and it talked in there about how doctors are left to quote guess what is appropriate for their 85 and 95 year old paper participant patients because they've not been studied and then he said the nice word is extrapolate but the reality is they're just making it up and I think that optimal care of all of us when we reach this age it's really going to depend on more and more studies allowing 80 and 90 year olds to participate so what is what are they being protected from with this hypertension is a real question almost every person who gets to mention this day and age in the United States especially tends to get the diagnosis of Alzheimer's disease or maybe Alzheimer's and vascular if they've got some kind of vascular history and yet we haven't really looked at the brains of most of these individuals so the autopsy study so 500 of our participants have already enrolled in the autopsy study we already have more than 300 of their brains and really I think some of the most interesting things that we were going to learn as always is from this study my father is a pathologist and I never really thought what he did was interesting but now I'm talking about it all the time so the first thing we did is if you had dementia how often did we find significant Alzheimer's pathology that was presumed to be the etiology and here we got what most people would predict in the red 60% of demented individuals who came to autopsy had intermediate or high levels Alzheimer's pathology that was assumed to be the cause of their dementia which was very fine until we looked at the non demented where 40% of the individuals who were not demented had intermediate or high levels of Alzheimer's pathology in their brain also in fact whether or not you had Alzheimer's disease pathology in your brain did not distinguish in any way demented from non demented and even when we looked at the few individuals there's about 50 or 60 individuals in whom we found no abnormalities in their brain except high levels of Alzheimer's pathology and exactly half of those had dementia and the other half didn't so the question comes up you're gonna be hearing a great talk from dr. Risa Sperling who's gonna probably tell you about prevention trials that are ongoing now including one that she's running called a for and these studies are in fact designed to take the individuals on the left side of the screen individuals who have no dementia but appear to have a V pathology in their brain as measured usually by a PET scan and see if we can influence the course of their illness ie can we prevent dementia in these individuals by removing amyloid or doing other other things but the question there's a new concept that's also percolating lately and has become of great interest to all of us a couple of years ago the niña and Molly Baxter at the cognitive summit meetings sponsored resilience reserve symposium where everybody talked about it and the most common definition of resilience that came out of that meeting in many publications was the individual who does not have dementia but has significant Alzheimer's pathology so I think we've got the same definition right now for two very different things when we see this is an individual doesn't really mean that they're in the preclinical stages of dementia or does it mean that they're able to withstand the pathology and to my mind at least in one individual person that can't be both maybe it can be both in the group of individuals who fill this criteria but for a single person it's either going to be preclinical Alzheimer's they're on the pathway pathway that many of you probably seen how many of you've seen this slide oh my god you know you go to too many Alzheimer's talks yes this is shown at almost every meeting and every talk and and most of you know it is the put together by cross-sectional data primarily but it's the notion that Alzheimer's disease is a chronic disease with a long preclinical phase and the red line on the left is the first thing that sort of starts going up and that's the amyloid load followed later on by tau and other problems with the brain and symptoms and the idea of the a4 study for example is that if we study people when they are in the preclinical phase when they have amyloid and are on the path that we might be able to make a difference but it's also possible that people that were calling preclinical is like that are actually really resilient I'm I really don't know the answer to this but some of the things that we've noticed in the non demented individuals in our study who have high levels of amyloid burden is that first of all they're more likely to be a bowi to almost a third of these individuals in fact are a bowi - April lipoprotein a as most of you know is the genetic susceptibility factor it's the strongest one we know about and I think the thing that's interesting at least in our study is that the e choose an autopsy have as much Alzheimer's pathology as the e-force but the only difference is the ephors are almost all demented and the e twos are almost never demented so a Polly too appears to be protective but not against the amyloid pathology which was what is what's the mechanism individuals in this in that side of the pie diagram who weren't demented but had high amyloid burdens in our study have higher education levels suggesting some component possibly of resilience or reserve and whether we've looked at it in terms of autopsy or imaging these individuals with positive amyloid scans or positive amyloid burdens on autopsy did not have faster rates of cognitive decline compared to individuals who didn't suggesting the possibility that in fact maybe they are resilient with which truthfully I wasn't so sure of us we started this I'm still not sure of it in fact about what is going on is going to turn out to be a complex story but I think a big part of the answer is going to be this my entire career I started out we would all say we were working in Aging and dementia and then after a few years of that we were all working in Alzheimer's disease and somehow both Aging and all cause dementia went by the wayside but all dementia is not Alzheimer's disease even though sometimes we use the words interchangeably and so we wanted to see what else is going on in the brains of these individuals so we looked at Alzheimer's disease which is up on the left but we also looked at hippocampal sclerosis micro infarct and white matter disease now the majority of these cannot be diagnosed during life I want to point out there is no clinical criteria that has been proposed really or works for identifying an individual who has hippocampal sclerosis they all get a diagnosis almost universally in Alzheimer's disease micro infarcts as a neurologist I was taught they're meaningless they're so little nobody cares they're too small to be seen with any kind of imaging and are purely an autopsy finding and then white matter disease the difference between white matter disease on him jingyan autopsies light-years but also not the diagnostic criteria so if we looked at these kinds of things and we compare individuals who had Alzheimer's or compared to those who didn't or hippocampal sclerosis compared to those who didn't you'll see in this slide the odds ratios for the different pathologies so the left is the far left is Alzheimer's disease and if you had high levels of Boyde plaques and tangles and compared to people who didn't you actually had a two-fold increase in your risk of having dementia so it definitely increased your risk but I want you to notice that it's the lowest increase on the entire slide because if you will if you had hippocampal sclerosis you had an odds ratio of 10 a tenfold increase in your risk of having dementia or leukoencephalopathy the white matter disease a 13 fold difference in having dementia so if I had a choice about what to happen to have in my brain right now there's no question Alzheimer's disease is the one to choose and most people don't think that but hippocampal sclerosis virtually universally demented white matter disease three or more micro infarct when we looked at just six slides to do our count if we found three or more which by the way properly represents the brain a total brain burden of 1,500 micro infarcts micro influx was strongly related there the odds ratio is 4 so 3 or more micro infarct says twice the risk of having high levels of Alzheimer's pathology and in fact although there's a lot of my crew infarcts in the brain really it's only the cortical micro infarcts that are related to cognition the white matter micro infarct did not relationship to cognitive decline or dementia now most people however especially in their 80s and 90s they don't only get one of these things so the majority of brains that we look at have several of different things and the number really matters if the pathologist essentially said we didn't find anything in this rain that's particularly serious or related to dementia there was still a 40% chance of having dementia if they found one thing which was most often Alzheimer's disease that went up to 60% but if they've got two or three it's basically a hundred percent of those individuals had dementia and the number was not only related to the likelihood of dementia but to the severity so these are many metals in those respective categories so if you have zero or one you had mild or moderate dementia but if you had two or three or four you've had a single-digit mini-mental showing very severe levels of dementia so with all this is the backdrop what we wanted to know is if one of these prevention trials succeeded what would be the effect of eliminating or reducing Alzheimer's disease in ninety year olds the fastest-growing segment of the population it's going to be 2 F 2 percent of the u.s. population by the time I retire 60 percent of the Japanese population and we constructed the following scenarios so here what you see is in deepening shades of salmon what we made the assumption complete elimination is the the bottom one the hot pink one where everybody who had high intermediate or low levels of Alzheimer's pathology were reduced to none to be white every plaque and tangle off the face of of 90 year old substantial reduction would be taking these individuals who are higher and immediate too low and so on and when we do that this is what happens today that is that about half of the cases of dementia in this age group would be taken care of but what it would do for the future is really what's done because by 2050 we will have more cases of dementia in 98 plus year olds than we have at all ages put together in the United States including 90 year olds right now and reducing that from about 4.8 million to about 2.3 million would really have a pretty profound effect on dementia in this age group but it still leaves the other half so the attributable risk of Alzheimer's pathology in this age and I'm starting to think even in younger ages although we kind of ignored the issue because most studies don't look at micro infarcts most studies see hippocampal sclerosis and kind of ignore it but I think that even at younger ages what what really is is going on is the idea that the expression of Alzheimer's pathology might be strongly tied to whether or not you're able to avoid these other problems micro infarct CIPA campus chlorosis and probably some disease actors and they're things that we don't recognize yet so I'm glad to say we are in the homestretch and in summary there's been there is and will continue to be a remarkable increase in longevity we've extended life expectancy by 28 years in the last century and I used to say that's not gonna happen anymore and we're not going to continue but now I actually feel quite differently even in the last few years we have continued to increased life expectancy I know you've seen some things about how in the United States for the last two years in a row actually there was for the first time not an increase but in fact if you take out opioid deaths and male suicides those are the two things that are driving those numbers because for the individual who's an 80 and not on opioids life expectancy is still going up the risk of dementia is really really high age is the strongest risk factor and that's true after age 90 and it's most likely due to not just Alzheimer's disease but a lot of other pathologies some of which we don't even recognize yet so many of these individuals however even with these astonishing rates of dementia remain resilient apparently even in the presence of neuropathology so we have individuals in our study who are still performing at levels they're probably quite similar to what they were doing when they were 60 and continuing to work and we signed up a Nobel laureate actually for our study at just last month so risk and protective factors and Prevention's and all sorts of things for all sorts of pathologies really need to have our focus over the coming years because even if we wipe out Alzheimer's disease we still have other ways in which we can we need to protect our brain as we age because old people aren't just bad versions of middle-aged or younger elderly and they have a lot to teach us so the most Thanks I need to give or for the for you coming here at 8:00 in the morning for the participants and their families who let us poking prod them and do all sorts of things and give us their brains the amazing staff and my colleagues at UCI and actually throughout a lot of the United States who are doing studies with us and thank you [Applause] [Music]

Channel: UCI CNLM

Views: 3,209

Rating: 4.7857141 out of 5

Keywords: dementia, memory, UCI, UC Irvine, university of california, kawas

Id: Ge0JtLhOBsA

Length: 39min 25sec (2365 seconds)

Published: Thu Jul 26 2018