In this presentation, David A. Merrill, MD, PhD, discusses different lifestyle strategies for dementia prevention such as the role of excercise, diet, blood pressure risk factors, and more.
it's a great pleasure to present my next colleague Dr David Merrill. He is a adult and geriatric psychiatrist. So rare bird. One of those rare geriatric psychiatrists in the world, shout out to any geriatric psychiatrist who may be tuned in or any geriatricians we know were rare breeds. But he is also the director of the Brain Health Center at P. And I. Uh So he's going to speak to us today about lifestyle strategies for prevention of dementia. All right, take it away. Dr Merrill. Thank you scott. Good morning, everybody appreciate you joining us. Uh So as scott was saying, I worked a lot with middle aged and older adults with mental health concerns have a special focus on memory loss and in particular prevention of worsening memory loss with aging. Uh So just a little housekeeping. I have no actual potential conflicts of interest in relation to this program and presentation. And um as a scientific example, I will actually be talking about consideration. Not the particulars but just considering off label use a hormone therapy and older adults with the purpose of dementia prevention really you'll see is it's it's more of as a scientific example, more so than actual clinical question of. Well, they're not to the risk benefit to move forward with that any case. Hopefully it'll it'll make sense as we go through this and go through these learning objectives to better understand the role of physical exercise for prevention of dementia. Getting to know the preclinical and clinical evidence for the role of diet in prevention of dementia and then also focusing on one of the things dr Porter talked about understanding the role of blood pressure uh and is one of the risk factors for dementia really, this is all to help you as a clinician to have a conversation with those who come to you families, patients loved ones and for yourself as well. Honestly, how to talk about things like the atlantic commission just came out with a lifestyle factor. Review of which factors have significant contribution to the risk of dementia is really an update and expansion of the Norton At all. 2014 study that Dr. Porter cited. So we have kind of an update and expansion of the risk factors from seven 2 12 and what is our goal here, essentially, you know, the brain, there's always a bit of a a different stance that's taken with the mind, the brain as opposed to the rest of the body. I think it's pretty self apparent, pretty self evident, that as we age, we want to keep our muscles strong, we want to keep our bones strong, we don't want to go into kidney failure or heart disease. But for some reason, the dialogue about the brain has gotten segregated into this Alzheimer's is the enemy as opposed to really like, we want to avoid brain failure. And so there's a whole movement in society and medicine and culture to understand that a real goal is to compress our morbidity and that is to shorten the period of time during which we're living in which were suffering from age related disease. And so you can see in this figure with the red period there further down along through the lifespan that we're looking to sandwich that period of age related disease to as small a wedge as possible in our life. And just as it's a applies to overall health. This applies to brain health as well. And so it's widespread the Alzheimer Association put together this slide showing that over time our brain function in those who end up afflicted. Because we know that by the age 85 up to half of people have full blown dementia. We tend to progress and we understand now that over the decades there's this progression with aging from a quote unquote pre dementia state which can be asymptomatic or pre clinical A. D. And those with genetic predispositions or family history of Alzheimer's two mild cognitive impairment and which were having significant deficits on testing. But we're compensating day today and then progressing on in the full blown dementia. And so for example the stage of M. C. I can last up to a decade. So the question is just if we take better care of ourselves going back to the health span concept can we push that point of progression out later into our own lifespan to extend our period of health and better function. And I you know I would argue that the answers are pretty resounding. Yes. But again, today's talk is about helping you have this conversation with your patients, yourself and your loved ones. Is that what what is the predicted results of intervening early to treat your body health in service explicitly of helping your brain help. We go to dermatologist for our skin. We do things like workout with a trainer for our aesthetics. But what about applying these strategies and techniques explicitly to keep your brain functioning better? The prediction of early treatment is that we will maintain our cognitive function later into time or later into our lifespan as opposed to Coming very end stage later late in the game. 10, 20 years into having noticed memory change and getting diagnosed kind of with end stage Alzheimer's to date, it's still much more feasible to protect the brain from degeneration than it is to repair it. And in fact, it's never one of the things dr Kaiser likes to say it's never too early, it's never too late. There are actually things you can do throughout the lifespan uh to improve brain function, protect brain health. And actually, I think I put the questions reverse here, It should be, is there evidence for all this lifestyle lifespan modification efforts And one clinician and result in response to his results which was showing delay of onset of genetically driven frontal temporal dementia by up to 15 years through increase physical activity. Was that, look if this were a drug we'd be giving it to all our patients and part of the challenge is is not as simple as taking a pill giving a drug. It's really changing behaviors. And so it's been known for some time now. Building off of what Dr Porter said that, you know, you don't have to take my word. I'm just in the clinic, I'm a clinician. But scientists national academies report show that in fact there is promising evidence enough to recommend at least three lifestyle factors. And this is like the most conservative body to say, look, we now know controlling blood pressure, increasing physical activity. Continuing cognitive stimulation helps prevent cognitive decline with aging and shows promise for preventing progression of mild cognitive impairment into full blown dementia. And this has been known for quite some time now. That's 2017. Uh In the last decade I was at the university here in Los Angeles U. C. L. A. One of the universities and we're doing a number of studies on samples of convenience and small populations of pre dementia patients, those with subjective memory loss, cognitive impairment. And we would assess things like their vascular health. Not not heart attack risk but stroke risk. And those with lower stroke risk, meaning really that they have better blood pressures or blood pressure control. So either lower measurement of blood pressure or proper use of antihypertensive medications. Things like hydrilla seen uh human denied. There's been evidence of disease modification for models of Alzheimer's individuals with better control of their stroke risk across the board. When we analyzed we tested their memories and and not just memory but also executive function, language, visual spatial tenant across the board. The brain is working better much the same way. If you're taking better care of your vascular health, managing your diabetes better your blood pressure, your kidney function panels will look better. It's very analogous. The brain is much more like the rest of the body than different. So I do tend to think of it as a special and Oregon similar story when we look at things like the levels of physical activity uh and and correlated those to their hippocampal integrity. The hippocampus being a key memory center in the brain. This is in individuals with pre dementia, some with april, we for genetics, some with family history, others with deficits in cognitive testing. Those who are going about two miles a day total through trackers whether it's a self report or Fitbit trackers or apple watches or Samsung. You know people who are keeping track of how much they're moving those moving more than two miles a day ended up with having thicker hippocampus. I and lo and behold they actually were also thinking better and more clearly on objective office based testing. So uh you know this helps patients this helps their family members. We actually did a study at UCLA of faculty and staff and you know I I have to say that as a participant of this program at U. C. L. A. Before is a three month program three times a week doing intensive function based exercising and with nutrition counseling over three months participants we were seeing that they're not only reporting improved metrics of physical health, physical strength brain function but also their mental well being was improving as well. So we studied and reported out on improvements in reported participants having less stress uh improved satisfaction with their social roles, their energy, increasing their sense of self efficacy being improved and their overall quality of life being better. And that that's something we're seeing again and again at our Brain Health center not just in our team members but also in our patients and caregivers that were actually able to improve quality of life through interventions that focus on changing the ways we behave to be more helpful. So how does this look in practice? Here we have a a younger but equally excited dr Kaiser demonstrating instruction of memory training during physical exercise. One of our our Liebe scientists and development in this area, Dr Sarah McEwen being the model for us to show that there's a synergy when you combine these lifestyle strategies. So combining exercise simultaneous with memory training tends to really light a fire in terms of your brain. So you do one or the other by itself, it helps a little bit you do them both together. And it's not only attitude but synergistic. We had a pilot study in about 60 pre dementia individuals and showed that in just eight weeks with combined dual task training where you're exercising and learning and practicing at the same time, memory performance jumped, you do the same thing separately and like, oh it's not enough. You haven't moved the needle, you haven't improved the outcomes. So we're really seeing that, creating innovative ways to improve the brain's health and function become synergistic. So I'm a psychiatrist, I will tell you there is such thing as a placebo effect. So even if you just gave a sugar pill, you will get improvement in memory cognition. That's the so called placebo effect. When we give something like the nepalese l memantine, there's a really small incremental improvement in that outcome. But as dr Porter alluded to not disease modifying, symptom improving just a little bit. What we found is that when you study using the same statistical types of outcomes meaning effect size, small, medium or large, doing signal single lifestyle interventions like cognitive training, physical exercise actually about doubles the effect size compared to the available placebos or medications. But then when you synergize those and you do them synergistically you start to get into really significantly large effect size for interventions, so so called extra gaming. Where your cycling and making decisions or something called interactive physical and cognitive exercise training. We actually have a trial in the center right now of that. It's an NIH funded study to develop a product where people would basically do this at home on their ipad while they cycle on a foot pedal. Er and There's been two or three studies is this already and you can see the effect size for this sort of synergistic combined intervention is up at about .6 as opposed to the placebo of about .1 in any case. What's the basis of this? How do you know that this is not just an amplified placebo effect? Well, one of my backgrounds is that I was a neuroscience PhD at the University of SAn Diego and we used to study things like environmental enrichment which if you think about it is kind of dual tasking for lab animals. So you have physical exercises improved through having jungle gyms and you also have a cognitive stimulation through exploring and giving them tasks and tests of where to find things. And so the data has shown that one of the mechanisms of increased activity with cognitive stimulation is upping something called brain derived neurotrophic factor. Brain drive neurotrophic factor is a cell survival factor and also plasticity factor that actually improves synaptic function in the brain. It prevents cell death And it actually uh combining this through other mechanisms elevation and BDNF can also result in augmentation of hippocampal neurogenesis with aging. And it's been shown in transgenic animals that there's less development of things like amyloid plaques in the brain which we know is not good for brain aging. Now, after looking at studies of animals, it's nice to get back into humans. Dr Porter talked about pet imaging of plaques and talking about a slightly different like and here pet imaging of plaques and tangles simultaneously work that I've done before has been able to show that we're able to track cognitive function and correlated to the levels of plaques and tangles in living subjects with pre dementia, either subjective EMC states. And that in fact, if you look at plaque and tangle burden in the brain and you compare it to proxies for health such as body mass index. Uh there is actually a correlation and that those with a more normal level of the B. M. I once you're into the sea state, you will have lower levels of plaques and tangles. Those with higher levels of physical activities again will have lower levels of plaques and tangles in EMC states. And I think what is perhaps even more impressive is that adherence to the mediterranean style diet across the board in pre dementia states, when you then look at the brains of these individuals, whether they have subjective memory laws, maybe 20 years before development of dementia or see a decade before the development of dementia. Those with a greater adherence to the mediterranean style diet have lower levels of plaques and tangles and uh it's just showing that across the board, there's multiple ways to get to improve brain health and when you start doing them together, you get better effects. Now. How is it that the mediterranean style diet could be contributing to body and brain health? Well, there's both kind of the observational effects of the diet. If you're eating the types of food that include fruits, vegetables, whole grains, healthy sources of proteins, liquid plant oils, things like extra virgin olive oil, salmon, cruciferous vegetables, association of the you'll have less saturated fat intake, you'll have reduced caloric intake. You have more vital nutrients and your microbiota Biota will be improved in terms of the metabolites on a more molecular basis. We know that this will result in improved insulin sensitivity, decreased levels of systemic inflammation and presumptively central inflammation in the brain, decreased levels of oxidative stress in the body and an improved nutritional status in the brain. It's actually just reported on November 12 at the clinical trials for Alzheimer's disease. That regular use of a multivitamin over the first two years actually significantly slows brain aging and older adults by about 60% or about a year and a half or 18 months worth of slowing that result came out last night. So I was not able to put it in my slides. But this dietary summary of the dietary guidance to improve cardiovascular health did come out at the beginning of this month. Um and so in fact these things are constantly evolving and constantly updating uh and you can share this news with your patients with your loved ones. You can keep up with yourself on on how what's the latest and greatest evidence for how to improve your brain health through lifestyle. Okay. So how does this look in clinical practice in the clinic? We're imaging the time course of Alzheimer's disease as we've talked about already this morning, hippocampal volume lowers. And Alzheimer's the natural progression of the treatment as usual. Is that over about The five years of early Alzheimer's state like the end of M. C. I. Beginning Alzheimer's you end up with about 35% volume loss in the Hippocampus. Something interesting started happening to me about 2015 as I more and more had patients implementing healthy brain lifestyle habits and activities. I started seeing cases of late stage M. C. I. That did not progress. And in fact we started seeing a reversal of hippocampal atrophy and patients. And it really led to the question like what is going on here, how is this happening? Um I wouldn't say that it's definitive unknown. It's not simple. We don't have a silver bullet but what we're appreciating more and more and other colleagues of mine in the fields were doing similar things such as in dr Richard ISAAcson. Alzheimer's prevention clinic at Cornell in new york is that we're combining healthy lifestyle with personalized precision medicine to create a state of brain health optimization. So today our seminars focus on systemic factors, lifestyle elements like sleep, diet, nutrition, stress management, exercise and then we're combining that kind of coached um ancillary service complementary strategies. We're combining that with targeted personalized precision medicine. And this is where I wanted to talk a little bit because I think in the medical field the mechanisms are more well worked out uh and and just kind of just fact of the matter, just give a basic science example of the effects of estrogen for example, on neurons in the brain. So animal models of early over ectomy show that when you remove the ovaries and you have no estrogen that the mitochondria shrink the number of reserve pool vesicles and neurons decreases the docked vesicles decrease in the active zone of the post synaptic density reduces significantly. When you replace estrogen, the brain characteristics in the neuronal level at synapses reverses and improves this correlates with working memory performance in testing and if you look at this further in terms of molecular pathways and amyloid precursor protein cleavage in the presence of estrogen, you're really pushing the larger amyloid precursor protein towards a cleavage pathway with alfa secretaries that results in soluble a beta, which you're not forming. Are you having minimal beta amyloid plaques as opposed to the absence of estrogen. You end up with lots of beta and gamma secretase cleavage and large level accumulation of excess, extra cellular beta amyloid plaques. Now the amyloid plaque pathology is joined with tau pathology in alzheimer's patients and also with market cerebral atrophy and hippocampal atrophy. So how do you get yourself to go down the normal pathway during aging versus the alzheimer's our best bet at this point is to combine healthy lifestyle with personalized precision medicine to create a state of brain health optimization. How do we do that? Well, we're curious, we assess, we help people optimize and then we repeat the process again and again. It's sort of the analogy if you were inside of a building with 36 holes in the roof, how would you stay dry? Well, you wouldn't be able to just plug one hole. You would need to patch enough holes. Hopefully all the holes to then keep the rain off your head. And in terms of body health function, we're looking at inflammation, metabolism, nutrients, growth factors, hormones, toxins were identifying those were trying to correct them. So hopefully the neurons end up being healthy cells as opposed to alzheimer cells. So we were working in our clinic the 1st 18 months, we were open from 2018 uh through the beginning 2019 Hunky Dory Global pandemic. Everything's uh shut down everybody's home in isolation. What do we do now? And it turns out social isolation is a risk for dementia. So, during the pandemic, what we've been doing is we've been pivoting, We've been trying to do this with people from their homes. So we ran a six month pilot pandemic dementia prevention group myself, claudia wang, which is one of our geriatric nurse practitioners along with a registered dietitian Amy Lee Amos and brain health coach Ryan. Glad we took a small group of patients. We gave them a curriculum that Amy lee actually created on a cognitive health. We had them watch the videos each week. We came together as a group. She answered questions about the lesson and then I gave them individual uh medical and lifestyle recommendations based on laboratory assessments to optimize their health. And we did this. It was basically from late 2020 into early 2021. And our assessments of these participants was a small group of patients with Five out of six with a .4 genetics and and actually all of them with family history. We joined with them in these multiple therapeutic episodes to coach lifestyle habits and then also to optimize their health. And over time we saw that each of these therapeutic episodes resulted in knowledge development, both in the clients when the patients. And then also interestingly in ourselves as providers, we were actually able to learn more how to implement a healthy lifestyle for brain health and then also to improve our health through precision medicine, health optimization And what's the result in six months we moved the needle. We actually did improve their cognition significantly in this small group 12, 12 cognitive domains tested were maintained. So there's no loss of cognitive function. And even with such a small pilot sample, we had a spatial planning reached statistical significance. Global cognition reached statistical significance. And you see verbal reasoning trending towards being significantly improved with the other areas maintaining and these are individuals who are on the path towards dementia. So what's our next move? Well, I would love to kind of replicate this. Obviously I'm just talking about this at a conference. I'm not saying that we've got this all worked out yet, but we would love to replicate this. We'd love to extend it, but we'd invite you to partner with us um in in increasing the diversity of our sample across the region and the nation and to also bring in new types of clinicians and coaches to to do this sort of intervention with people. I think there's a kind of a road map for health optimization. If you have an interest in this, let me know that does know. And so we're really looking to grow this with the realization that in fact uh dementia prevention, intervention and care at this point in time is very significant approach. Uh it's now understood that dementia could be prevented or delayed in 40% of cases by addressing 12 modifiable risk factors that includes the seven factors that have been known for some time. And then additional factors that have been identified more recently where potentially modifiable risk factors are thought to be the attributable risk For a certain percentages of cases, about 40% of cases in total. The most recent update added air pollution as a risk factor. Um and then believe traumatic brain injury also as a risk factor recognized and excessive alcohol consumption. But you can see here that these are factors that can be addressed throughout the lifespan through uh promoting better access to education early in life, avoiding things like traumatic brain injury through midlife, treating things like high blood pressure, body mass index, um in midlife and then in late life, making sure that we don't end up with social isil. Ization, isolation, that we remain physically active and that we are not doing things like having excessive exposure to stress or smoke these approaches. They've been into different mechanistic ways of reducing risk for dementia. You have some of them that are reducing the neuro pathologic damage that results from these activities such as amyloid deposition, tau tangles, vascular inflammatory changes and then you have other activities that really increase and maintain something we haven't talked too much today about which is cognitive reserve. And then my favorite approaches exercising treating your mental health, avoiding excessive alcohol intake. They actually address both reducing neuro pathologic damage and also increasing cognitive reserve to prevent dementia. So again in wrapping up here before be happy to take some questions. The whole goal is to slow or prevent progression along this spectrum of disease With aging where you're going from preclinical to EMC two full blown dementia uh which is basically diminishing or destroying your quality of life, reducing your health span in a way that is really devastating for patients for families. It's very difficult as a practitioner. And so this is our goal is to keep working with individuals to help them identify where they can modify their behaviors to improve their health span. So they achieve optimal longevity and live a life free of age related disease and really do as best they can as they get into older old age. And this is something I'm not doing on my own. It's working together better in partnership. This is just within our Brain Health Center. Our team has grown From zero at the beginning of 2018 to now. I've kind of lost count. There's 50 plus individuals who are working on all levels, clinical care, scientific exploration, administrative optimization and um and the like, So I've got 20 seconds left on my clock, nope, that's 2020 seconds left. Thank you very much. Thank you. Thank you. Excellent. We had the, you know, this is great. You can go on all day. I love it. But unfortunately we have so many questions that came in, I don't think we'll get to all of them, but they're great questions actually. I was thinking of a slide a couple slides ago, you had talked about collaboration and doing this as a team. And so I wanted to highlight this question because it comes from a neurologist who is also a yoga teacher. So give us a call connect. We'd love to meet a neurologist who's also a yoga teacher. And they are specifically wondering about data on traditional yoga practices for cognitive decline. Because you highlighted probably more of a cardiovascular aerobic strength type mechanism. But what about yoga and cognitive decline? Absolutely. Mindful. Physical exercise is very important. That is physical activity with the explicit intent to reduce stress. And there's a number of excellent studies. I would direct you towards dr Helen Lubetzky. She's an investigator at U. C. L. A. Who has reported on improvements in cognitive function and pre dementia through the practice of yoga. Excellent. And what's your take on brain games? You know I'll leave the brand names out but the kind of things you can buy a loved one or a patient understood there is good evidence that maintaining cognitive stimulation um will help with brain aging. The disappointment has been a lack of transfer effect. So it's the old like if you practice cost for puzzles a lot you end up really good at crosswords. But do you prevent dementia just through doing that? No. Um That was kind of why you and I we've gotten into this synergy izing strategies of combining approaches. So if there's a cognitively stimulating activity you like do that and combine it with physical movement. Yoga is actually a great example. Dancing, gardening things like going going for walks with your loved ones in nature. So combining approach is not necessarily you don't need a new software, a new platform. You really need to engage in activities that you're enjoying and that will help you help your brain. So just to give a flavor of some of the questions because I think we're I don't want to cut too much into the break. So I want to go to to that. I think it would be good one. Really tough 11 softball. But so there's great stuff about blue zones and epi genetics. And there's questions about intranasal insulin and questions about like how do you reconcile if estrogen presence of estrogen is associated with reduced amyloid, why do more women get alzheimer's? I mean awesome questions here. But the tough one because there's good fats, bad fats. What about looking at lifelong vegetarians, uh do they have reduced incidence of dementia? Anything about a vegetarian diet? And uh dementia? Yeah. Well uh you know this I think of Loma linda where they have a large population of vegetarians who have done well with aging. I think of blue zones or certain behaviors and habits lead to superior aging or better health outcomes. I think the evidence is growing that focusing on a plant based diet where you're minimizing animal derived saturated fats is better for cardiovascular health. And it it seems the reason we'll end up helping for brain health as well. Um so I think it's it's another push to consider uh and just to work on eating whole foods eating foods that are free of toxins and just all right to end with a no brainer, so to speak. One where there's no controversy. What about meditation? Mm. Yes. I would definitely suggest that during the break you go take a meditative break. Um It's similar where these trials. Uh it is great to build the evidence base. Will there ever be a definitive phase three clinical trial where meditation alone prevents dementia for everyone? No, but I think it's pretty hard to argue that you will not be more peaceable and happier and less stressed if you're able to find out a way that works for you as an individual to lower your stress. Okay. Excellent. Excellent. All right so we're going to take a brief break. Thank you dr Merrill and then we will be back with dr Gordon Ethan.
