Well, good morning, folks. Nice to see you bright and early here at 8 a.m. My name is Art Wallacek. I'm at the University of Wisconsin, and I'll be moderating this session. This is part of a new series, a new track that we're trying out at the APA Annual Meeting, so we'd love to get your feedback about this. This is the clinical updates track, and so this is meant to be practical and evidence-based information that you can use in your own practices. I'm absolutely delighted to welcome and introduce a couple of terrific colleagues, really major thought leaders in the field of geriatric psychiatry, Drs. Layman and Forster, and I'll introduce them each right before they present. So, first up is Dr. Layman, just pull up my notes, Dr. Layman's just been a terrific colleague and collaborator. I'll give you sort of the official story here, but just personally has been a terrific person to work with. Dr. Layman is the inaugural Patricia B. and William T. Bright Professor of Mental Wellness and the Clinical Director of Geriatric Psychiatry and Neuropsychiatry at the Johns Hopkins University School of Medicine. She's an Associate Professor in the Department of Psychiatry and Behavioral Sciences where she oversees geriatric psychiatry clinical services at the downtown hospital and Bayview Medical Center. She directs the Geriatric Psychiatry Outpatient Clinic and Geriatric Psychiatry Fellowship at Hopkins. She is a national leader, truly, in geriatric psychiatry and in geriatric psychiatry education at all levels as well as non-psychiatric clinicians. She's interested in improving medical student and general physician education in geriatric mental health. She directed the Psychiatry Clerkship at Hopkins for 15 years and is a former president of ADEMSEP, which is the Association of Directors of Medical Student Education and Psychiatry, which is how I first got to know Dr. Layman. She currently serves on the board of the American Association for Geriatric Psychiatry. She has received numerous awards, including AAGP Educator of the Year. She's presented and led symposia at annual meetings of AAGP and ADEMSEP on topics related to medical education, aging, and ageism. In addition, she's published articles, book chapters, online educational materials related to a variety of psychiatric disorders in geriatric patients. She is co-editor of a recently published book with Dr. Forrester, Bipolar Disorder in Older Age Patients. So fantastic bona fides, and it will be a terrific presentation. So thank you, Dr. Layman. Well, good morning. I'm delighted to be here this morning with you and talking with you today, also with my colleague, Brent Forrester, about the assessment and management of memory complaints in older adults. I'm going to present both of our disclosures for you, and you can see Dr. Forrester has a number. He's currently the immediate past president of the American Association for Geriatric Psychiatry, and you can see the areas where he's received grants and research support over the past three years, as well as consulting he has done. I do want to mention to you that he will be discussing unapproved or investigational use of pharmaceutical compounds during the portion of the talk that he's going to be giving today. I don't have any relevant disclosures or financial ones related to this talk. So our learning objectives this morning, we both hope that by the end of the session, you will be able to identify key differences between cognitive changes that are associated with normal aging, those that might signal a cognitive disorder. We hope that you'll be able to discuss the appropriate office workup for a patient who is in your office in the chair and seems to have subjective cognitive complaints either brought to you or that you've become concerned about, that you'll be able to describe differences in presentation between the most common types of dementia that may affect our patients, that you'll be able to discuss the FDA-approved pharmacologic agents that we currently have available for treatment for cognitive symptoms in dementia, and also be able to describe evidence-based strategies that we know are helpful for both maintaining and sustaining brain health and hopefully preventing cognitive decline. So just as a point of background, this is a slide that is put up by the Alzheimer's Association and it's focused primarily on Alzheimer's disease, but really what it presents to us is just in a little picture here, a sense of the scope in terms of numbers, that we're talking about over 6 million individuals who have Alzheimer's or other forms of dementia at this time in the United States. Then you think about the impact on families. On top of that, there's over 11 million Americans who provide unpaid care for people. These are family caregivers. These are friends. Their lives are impacted by dementia. There's a huge financial impact of dementia and when you think about the cost. And then we also, thinking about this, dementia is also an area that's affected by disparities in healthcare as well as so many other areas as well. So this is a huge area and a huge impact in multiple domains. So whereas right now over 6 million Americans have Alzheimer's disease or other types of dementia, well this number is expected to double by 2050 because we are right in the middle now of a huge demographic shift in this country. Between 2010 and 2020, the percent of older Americans over the age of 65 was stagnant at about 12% of the population, but it's been rising significantly since then. And right now, we are up to about 17% of the population who are over the age of 65 and by 2030, it's going to be about 20 or 21% and continue to increase. And the reason, of course, is because we are experiencing the aging of the baby boomer population, that very large demographic that was born between 1946 and 1964. The leading edge of the baby boomers turned 65 in 2011. And so, in addition, we have about 5 million Americans who have what we call mild neurocognitive impairment and that kind of, which we believe a good percentage of those individuals will progress to dementia and even those who don't have cognitive issues that they need to contend with. And so, with the aging of the population, all of us as psychiatrists, unless you only do child psychiatry and adolescent psychiatry, all of us as psychiatrists are going to see more older patients who are concerned about their memory. And it may be the patients you have followed for a long time, have been with you for a number of years, maybe who came to you because of depression, bipolar disorder, schizophrenia, anxiety, whatever it may be, and now you're concerned and they're concerned about their memory changes. And I've had that in a number of my patients that I follow for a long period of time. As well, you may see patients who present to you at a later point in their life and maybe the presenting complaint is anxiety or maybe it's depression or maybe it's memory and they're worried about it. And then you begin to worry about memory. We know that subjective memory decline may be an early sign of a serious cognitive disorder, but we also know that subjective sense of memory loss isn't always dementia. It could be other things. So how do we tease it out? So it can be challenging, but we want to go over an approach to that and how you would be able to think about it in the office this morning. So I'm going to speak first and I'm going to be focusing with you on recognizing cognitive decline and impairment and really focusing on how you kind of tease out this aspect of diagnosis. I'm going to be focusing with you on initially kind of differentiating normal changes in memory from those that might be more worrisome, reviewing with you what should be an appropriate office workup if you are concerned about memory complaints and thinking about those, quote, treatable causes and distinguishing different types of dementia and also how you would distinguish them from other psychiatric conditions. So let's begin by first just talking about what is dementia and reminding you that when we talk about dementia, remember it's not a diagnosis, it's a syndrome, right? It's a syndrome and it's a general category of affecting thinking and memory. So often I have patients who say, oh, Dr. Lehman, what's the difference between dementia and Alzheimer's disease? This simple fact I think is really so misunderstood in the population. People don't recognize Alzheimer's as an example, a type of a dementia. It's also important to remember that the diagnosis of dementia requires a couple of key things. First of all, a change in two areas of cognitive functioning from a previous much higher level of ability and it has to cause impairment. So there are many specific causes and types and I'll be talking more about that. You would think that dementia should be obvious and it isn't obvious and I'm going to talk to you about the reasons why and in fact, this is a paper that came out in 2009 and it really addressed the fact that dementia is so often missed by primary care physicians and you could probably publish the same paper today in 2022. It's still a problem. It's a problem for primary care physicians and I'm mentioning that first because of course when we think of cognitive impairment, usually our patients might present first to the primary care physician and you'd think that that individual would likely pick it up first, but they might not pick it up first. You might be the first one to be raising the question and there's a lot of reasons why. First of all, to think with me, dementia happens gradually in most cases and it's insidious and there's changes that happen gradually over time, right? And as those changes happen, they don't all change at the same time and so in fact, some early changes, which might be ones related to executive functioning or to memory, might present first and might be early signals, but language might be preserved, particularly in Alzheimer's disease and social skills. So if you think about a typical primary care appointment, which might only be 12 to 15 minutes and that amount of time when the primary care physician is focusing on going over medications and quickly going over a lot of different problems that the individual has, if their language is preserved and the patient doesn't bring it up and they may not be aware of it, it might be completely unrecognized, especially if they don't do a structured cognitive exam. And if they're there with a spouse, well spouses are frequently compensating, answering questions as well so it could be completely missed and even more so if the individual is living alone. But there might be signals and so there might be things that might come up, for instance, the individual might have frequent car accidents, misjudging distances in parking lots, kind of little fender benders, getting lost on familiar routes and taking the wrong turn of going to the barbershop, the beauty shop, church, the grocery store, things that they used to be able to do. Missing or forgetting appointments or having difficulty cooking, burning things, leaving things on the stove, not paying maybe a missed bill, missing that water bill, the electric bill, having trouble with appliances more than they used to be able to do. And then it might be family might notice we've said something many times and dad or mom are repeating questions, they're saying they don't seem to remember, misplacing items and being unable to retrace your steps and find where you put something, losing track of the day or date or season, that could be a pretty concerning one, poor judgment or decision making. I'll tell you in my own family, my uncle did not realize that my grandfather had a serious cognitive impairment because he was living alone with my grandmother and they were still actually going to their little shop every day that they worked out until the day he gave away the car to the mailman. And it had 5,000 miles on it and it was a really nice car and why he had that judgment decision that he gave the car to the mailman, it may be because in his early life he was a mailman himself and had delivered letters and he felt an affinity for the mailman but that made people think, gosh, why did dad do that? That doesn't make any sense. So sometimes it's a really significant poor decision making. I mentioned people might be confused in familiar routes but a really frequent signal is a lot of anxiety in an unfamiliar situation, more than it might normally provoke or feeling overwhelmed by something a little bit unfamiliar. In the office, if you have the individual and they're there with another family member, whether it's a partner, whether it's a child, you might notice something that my geriatrician has called to me and I didn't make this up but a friend of mine who's a geriatrician called it the positive head turn. That's when you're asking a question of the individual and they're looking over to their left where the spouse is or where their son or daughter is for the answer and to confirm it. If you see that happening a lot, the positive head turn for confirmation, that could also be a signal. And so often it happens that particularly when couples are together for a long time, they end up compensating for each other. And so cognitive impairment might be unrecognized by the adult children until one spouse passes away and is deceased. And all of a sudden they say, oh, mom was doing fine until dad died. A week later, she probably wasn't. But because they were working so well as a couple and dad was compensating, you didn't realize the changes were happening gradually. Before we can talk even about recognizing the different types of dementia, it's important to review with you, there are normal changes with cognition that happen with age that we don't consider to be precursors of dementia. This is very important to recognize because I'm going to tell you in my practice, all of my patients over the age of 60 or 65 are worried about their memory. A lot of them have taken care of their parents who have had dementia and they're worried that it's going to happen to them. And so any little signal that they notice in themselves that they're starting to get forgetful, they say, oh my gosh, is this normal or is this Alzheimer's? So what is normal with aging? Well, with age, it does take a longer time to process and digest new information. There's slower psychomotor speed. Older adults can multitask. It's harder to do that, but it can be done. And there's this aspect of difficulty with what we call noun retrieval. That word is there. What was the name of that actor? What was the name of that film? I just saw it. I just saw them on TV. I know what it is. I know what it is. And then it might come up a couple minutes later, a couple hours later, or the next day. It is not forgotten. This is really important. It is that it's a difficulty with word retrieval from longer term storage. That can be totally frustrating, but it's important that when your patients bring this to you, if that's all this is, you can reassure them that that difficulty with noun retrieval is normal after the age of 50. Happens to just about everybody after the age of 50. There are some aspects actually of thinking which stay the same or improve, and vocabulary actually is something that often improves throughout the lifespan. So I'm showing to you a couple of ways maybe even to distinguish what might be normal aging from Alzheimer's. And you'll see it's often in a matter almost of degree, because while we all might make decisions and once in a while that we regret, this really significant poor judgment and poor decision making that seems really out of bounds might be more for Alzheimer's. While occasionally we might say, I say this often myself, oh gosh, I missed what the date is today. I would only have a 29 out of 30 on my mini mental state exam. That's just how a geriatric psychiatrist might say. But you know, we're forgetting it once in a while. We don't really worry about it. Sometimes forgetting a word once in a while. We all lose things from time to time. We park the car and we wonder where is it in the parking lot or where did I last leave my keys? But not being able to retrace your steps, doing this over and over again, real significant difficulty doing things like managing a budget, really losing track of the date or the season. Those are more significant changes. So we recognize that most people go through a period what we would call a mild cognitive impairment, DSM-5. It is described as mild neurocognitive disorder, which often is a precursor to dementia. Now here are the key elements that you'll notice. There will be usually a subjective complaint. The individual themselves might notice that they have some sort of decline, usually in one or more areas. It might be memory, executive functioning, language. The cognitive decline is measurable. It is measurable on some sort of cognitive test. So it's a subjective sense, but it's not just a worry. It is a measurable change, but this is key. No impairment. No impairment in social functioning. No impairment in their occupational functioning. Individuals at this stage can compensate. They can write down lists. They can use their list. They can look every day on the calendar. They can find ways to compensate. When we're talking about the major neurocognitive disorders, it's a different element here. DSM-5 describes dementia as one of the types of neurocognitive disorders. It could include something like an amnestic disorder, which is only memory, and I'm not going to really focus on that today. But here, again, there's going to be concern that there's been a significant decline in cognitive functioning, but as well, a substantial impairment that's measurable, and deficits have to interfere with independence in everyday activities. It cannot be occurring in the context of delirium, or there isn't another mental disorder that better describes it. You'll see, just to refresh your memory, the differential diagnosis of dementia is large. There are a lot of different types of dementia. Many of them would be ones that you probably might not necessarily come to the attention of the psychiatrist and might be known in the family, such as Huntington's disease, which we know is heritable, TBI, physical traumatic brain injury. That's not going to be so difficult to diagnose, because there will be some sort of head injury that will have happened to an individual. So I'm going to really focus with you on just a few of these on the list today. I'm going to talk about Alzheimer's, vascular, dementia with Lewy bodies, and frontotemporal dementia. Of these, Alzheimer's is the most common, affecting two-thirds, and vascular, depending where you read it. Some people say it's the second most common, maybe 10 to 12 percent of the population. But to be truthful, vascular changes probably also occur in Alzheimer's as well, as we're beginning to understand it. So actually, the rates of how it contributes to cognitive impairment are probably considerably greater. And dementia with Lewy bodies may be 5 to 10 percent. So what can we say about Alzheimer's disease? As I mentioned about the most common cause of dementia, early symptoms are always going to be impaired short-term memory. And it really goes through a progression of a kind of a continuum, where the first changes are executive functioning and short-term memory. Difficulty remembering what was done within the past couple of days, whereas long-term memory is more preserved. Later on, there will be language changes, and then there will be apraxia. And finally, in the really final stages, agnosia, not recognizing familiar people, not recognizing familiar places, not thinking your home is your home. So early on, though, there will be also executive dysfunction, which is difficulty. Executive functioning is problem-solving, anticipating consequences, sequencing. And so people have difficulty with organizing. And this is really interesting, which is many individuals lack awareness. You would think it's always going to be obvious. And for some individuals, it's painfully obvious, painfully obvious. I have a patient who was so painfully aware of her difficulty with memory and word retrieval that got worse over time. She was very prominent in Baltimore, really a leader in the community. And her occupation was on the board of different places and gave lots of talks. And she started withdrawing from all of her community and leadership work because she was so embarrassed that she had difficulty stringing words together and talking. So it was so demoralizing and difficult for her. But other individuals have no awareness and don't even appreciate this, what their deficits are, which could be even of a greater concern. And depression may be part of the prodrome. Very interesting. This goes beyond the scope of what I can discuss with you today, but some really current work is really indicating that a new onset, late-life depression, very often is not a risk factor for dementia, but might be an early prodrome of dementia, actually. What do we know about the pathology? Well, we know a lot about the pathology, actually. Alzheimer identified it early on in the 1900s. And we also now know that the changes of Alzheimer's can be detected in the brain and spinal cord 20 years before the individual has any cognitive symptoms, which is amazing. And we know that, yes, you've heard about them. There's the beta amyloid, which are the extracellular plaques, and tau, which forms intraneuronal neurofibrillary tangles, are the key pathologic findings we have in Alzheimer's disease, and when we believe it's somehow due to an imbalance both of production and clearance in the brain, and that ultimately, ultimately, cognitive impairment comes not so much from these substances as the fact that there is synaptic failure of the communication between neurons and the synapses. So this just is a picture, again, of Alzheimer's, and you can see that these are, let me see if I can, here's a, these are a picture of plaques, and these are the tangles here, intraneuronal tangles. Vascular dementia is a broad category, and we can see that vascular changes and impairment can happen from multiple small strokes, where the ischemia actually could be silent or unrecognized or severe to severe, actually known strokes. Classically, we think of this as stepwise progression, and that individuals are well at a certain level for a while, and then they decline when something different, when there's an accumulation of more insults to the brain, and certainly want to think of this in individuals who have a lot of risk factors, hypertension, diabetes, particularly if they're longstanding and may not be so well controlled. Dementia with Lewy bodies is very interesting, and we're recognizing this to be, it's often difficult to differentiate from Alzheimer's because it can be gradual. What we see, again, are these Lewy bodies, which are misfolded protein, alpha-syn-leuclan, and Lewy bodies, as you know, are a hallmark pathology of Parkinson's disease, but there they are really in the substantia nigra, whereas in dementia with Lewy bodies, we see Lewy bodies widely throughout the brain and throughout the cortex. You can have dementia in Parkinson's, maybe up to 40% of individuals do, but dementia in Parkinson's happens one or more years after the onset of motor symptoms. So classically, there's the motor problem gets diagnosed first, and one or more years later there's dementia, whereas dementia with Lewy bodies, they happen pretty much simultaneously. There's the onset of Parkinsonism and cognitive decline, and this is really interesting, usually very vivid, silent visual hallucinations. Sometimes they could be auditory, usually visual, and frequent unexplained falls due to autonomic instability. Frontotemporal dementia is an early onset, usually affects people between the ages of 50 and 70, and unlike Alzheimer's, the primary change is personality or language, not memory as much. That can happen, but later on in the course of the disease, and the personality changes can be drastic. An individual might be using really foul language that was uncharacteristic for them. There may be impulsivity. There might be preoccupation with pornography or gambling or behaviors that really were uncharacteristic of the individual, and because it happens in the prime of life, this can cause so much stress and challenges for families because you can imagine these individuals often have young children at home. They're in the prime of their working years. So I put together a little slide here for you, kind of differentiating these four different types. How would you kind of distinguish between them in a couple of key areas? And you'll see that in terms of onset, the thing, as I mentioned to you, vascular is going to be either a sudden change or stepwise changes, whereas the others are more gradual. In terms of cognitive symptoms, for vascular, it might depend on which areas of the brain are involved. You might have someone who has relatively preserved language, but lots of difficulty with math and calculation, depending on what areas are involved. But with Lewy body, again, you're going to see these visual hallucinations in memory, and for frontotemporal dementia, executive dysfunction, personality change, disinhibition. In terms of motor change, really, you're going to see this Parkinsonism at the onset with Lewy body dementia. And in terms of progression, Alzheimer's disease, most people say the lifespan is about eight to 10 years after diagnosis. It can be up to 20 years, depending how early it's picked up. A question that sometimes comes up, and this would be if you were ever asked to evaluate somebody with nuanced cognitive impairment, for instance, you're in an emergency room, you're the psychiatrist in an emergency room or that kind of a setting. Cross-sectionally, an individual with dementia or delirium could be difficult to differentiate, but you're going to want to really think about the hallmarks of delirium, its rapid onset, really rapid or subacute changes. There's those fluctuating levels of consciousness. At one point, someone might seem lucid. A couple hours later, they're very confused. And the hallmark feature is inattentiveness. They can't follow you. They seem to be easily distracted, maybe by other things that are going on in the room. And this is a medical emergency. It really requires immediate workup to treat whatever is the underlying medical cause. Our patients who do have cognitive impairment are at high risk for delirium. What about depression? And this happens so often that there seem to be overlap in symptoms, then they can be difficult to differentiate, because individuals who have dementia often have a loss of interest in activities. They might withdraw socially from groups or organizations they've been involved with. They have trouble concentrating. So how would you distinguish, well, is this depression or is it dementia? Because as we know, many older adults with late-life depression don't say they're sad. Some might say they're sad, but some don't say that they're sad. And so we really look for other changes in diagnosing late-life depression. And for me, the hallmark change for a late-life depression is anhedonia, even more than subjective reports of sadness. Anhedonia, which is not just a loss of interest, it's a loss of pleasure. Not enjoying the things you used to enjoy. Whereas individuals with dementia might have more apathy. They're not so interested in it, but they're kind of, you know, could take it or leave it. It can be tricky to differentiate, is this really anhedonia or is it apathy? But if you can do that, that's very helpful. Because in both depression or dementia, there can be a diminishment of self-attitude in both the onset of symptoms, symptoms could be gradual or abrupt. I find a couple other helpful clues are if you do cognitive testing in your office, which I'm going to encourage you to do, a brief cognitive exam, individuals who are depressed are going to give up. They're going to say, that's too hard, I can't try it, I don't want to do those serial 7 subtractions, Dr. Layman, I was never good at math when they went to college, and I know they were good at math because they did the SATs. So, you know, whereas individuals with dementia might actually try it, give wrong answers and won't be aware that they're giving the wrong answers. They won't notice it. And then as well, variability in symptoms. We know when patients are depressed, right, they have sort of a diurnal variation where the mornings are awful for them. They wake up in the morning, they're disorganized, they're anxious, it's hard to get their day going. Sometimes they feel better later in the day, and it's the opposite for dementia. We often hear about the sundowning people getting cognitively worse later in the day. So you're concerned about the patient, maybe a family has alerted you in an email, I'm really worried about my husband or my wife, there's things I'm concerned about. You might notice in the interview yourself, particularly if the patient doesn't have that self-awareness, that if you're trying to pin down a history or get sort of a chronology, it starts to get a little vague. If it's a new patient to you, sometimes patients actually kind of behave as if this wasn't so much a medical appointment as social, and they might sort of chit-chat and ask you questions about your family or want to get to know you, and that can seem a little bit off. If you ask them questions, the individual, and they don't know the answer, sometimes people are a little defensive, you know, of course I know that, or they get a little defensive, even with cognitive testing, so it has to be done very respectfully. Crucial questions are always, as they are with everything we do in psychiatry, the history is so important. We know how important this is for all aspects, particularly for when you're concerned about dementia, and really identifying those areas of cognition that are affected, and the time course over time. Like with everything we do, we really want to take, really think about this comprehensively, review the neurologic history, go over medications. We know that a lot of older patients are on a lot of medicines. Sometimes polypharmacy can be causing cognitive change and confusion, especially anticholinergic medications. Don't forget to ask about substance use history in alcohol, particularly in these times. We are seeing rising rates of alcohol use in older adults that have been going on in recent years, and particularly since the pandemic, it's gone up even more. Don't forget that that could be a cause of trouble with cognition. I just saw a patient about a month ago, it was referred to me, somebody, a physician actually, and her physician was worried about her memory, and I found out that she and her husband were polishing off a bottle of wine every single night since the pandemic, and they were both home alone, and doing telework, and really getting her to totally change that improved her cognition a lot. You really want to do, of course, a good mental status exam and a cognitive exam, and to remind you, the laboratory tests, again, that we think about would be doing thyroid studies, B12 folate, complete blood count, a comprehensive metabolic panel, if appropriate. You might want to screen for HIV or for syphilis, and this is really critical. As much as possible, when there's a concern about memory, see if you can talk to another informant. I think that's really important, to get a sense of the chronology, and the level of impairment of what is going on. I had a patient of mine who was a faculty member at Hopkins, and it was his wife who noticed the changes first, and she was concerned because he was a PhD scientist, and she was his editor for his papers, and she said, I noticed he wasn't writing the same way, and I was having to do more editing, and she brought it to the attention of the primary care physician, who in the primary care appointment didn't notice any changes, but the wife was right. When I took her observations and assessments seriously, and as I got to know him and followed him over time, she was right. He really ended up having a progressive dementia, so listening to the family is really critical. In terms of what to do for an office evaluation of cognitive assessment, I often do the mini mental state exam, which is very widely used. The mini cog is super short. A lot of physicians like to do that. It's very, very easy to do. You just ask the patient, give the patient three items, and you want them to repeat them and remember them. Then you ask them to draw a clock. You present them with a circle and say, I'd like you to please put in all the numbers of the clock as they appear on a clock on the wall, and after they do that, you ask them to put the hands of the clock to read 10 past 11. Then you ask them to recite to you back the three words you would ask them to remember before, and the scoring is out of five. They get one point for each of the three words they remember, and two points for the clock, one if they got all the numbers correctly spaced around the clock, and one if they put the hands in correctly. If they get a four or less, it just screams that there could be cognitive impairment, and three or less, you'd be very concerned and want to follow up further. I use a lot the Montreal Cognitive Assessment because the MOCA is a very good test because it picks up on early changes, particularly for people who are highly educated, and it picks up on executive dysfunction, which the mini-mental state doesn't do. When might you consider more detailed neuropsychological testing beyond just an office screen? Because again, these just screen for impairment. They don't give you a diagnosis, of course. I would say any time something just seems, if it just seems off to you, if there's something atypical, and especially if there's early onset and you think there's some sort of cognitive impairment here, and it's somebody who's really young, and particularly if you're thinking it might be frontotemporal dementia, I think a good neuropsychological battery is incredibly useful in really teasing this out. Particularly if you're really on the fence, I'm not sure if this is, you know, what's going on. Something's unusual. Is it psychological? Is it psychiatric? Then I think it'd be very helpful to refer for a comprehensive battery. One thing to really be thinking about with older patients is safety. Whenever there's a concern about memory, this goes through my mind. If I'm worried about cognition, I'm worried about these four areas that impact safety. I'm worried about driving. I'm worried about medication management, the ones that I'm prescribing and the ones that their primary care doctor or their cardiologist are prescribing. I'm worried about money management, paying bills, and I'm worried about eating and cooking food. I mean, all of these are complex tasks, and if they're not concerns in the beginning, they will become concerns over time, because over time people will develop impairment in these key areas. So I'm not doing the driving evaluation, but over time, if I'm concerned, I will recommend to the patient and the family to have a formal driving evaluation, and this is going to vary depending on your locality of where you are, what's available. Where I am in Baltimore, there are two different hospitals where they will do a good driving evaluation. They start first with like looking at a movie or something like that, and if they feel somebody has sort of passed that in terms of reflexes, they'll take them out in a car on a route and actually evaluate them driving in the car. And if they don't do well, they will report it to the Motor Vehicles Association. So, I mean, knowing what your local resources are will be very helpful to you. I recommend all my older patients, I mean, whether they have cognitive impairment or not, to use a weekly medication box to organize their medicines. Of course, this will not work if somebody's confused about the day of the week or they have such short-term memory that they don't remember that they already took their pills. So sometimes you need to really talk to family to take over giving the medication and take charge of it. If there's difficulty with meal preparation, you have to think about things like Meals on Wheels. And before the pandemic, I was often helping families think about things like medical daycare. They're just starting to reopen in Baltimore. We'll see how that goes. So in working with older adults, it's so important to identify their family supports and talk with the family. Maybe this isn't necessarily always the first conversation, but over time, is in-home support needed? Is it safe for them to be alone? Maybe to thinking about that advanced care planning and also to recommend that they get support for themselves. The Alzheimer's Association has groups online and they're a fantastic resource. So I really think, for me, the work of working with patients, the journey is really just beginning or taking a new and different direction when I'm worried about memory impairment. And this really distinguishes us as psychiatrists. And this is why I think we have such an important role. Maybe we're going to be partnering with a neurologist or a primary care physician, but we know our patients and their families. We spend the time with them. We know the toll that it takes on them and emotionally how they're adjusting. And this is a condition that changes over time. So their needs for emotional support, for physical changes, for planning, for safety changes will change over time. And as rates of neurocognitive disorder and dementia are rising, I think this is going to really be for all of us to be more familiar with. Again, whenever there's a concern about memory impairment, think about the thorough assessment and having a systematic approach, including safety and involving family. So thank you very much. I'm going to stop and ask you to hold whatever questions you have and turn this over to my colleague, Dr. Forrester. That was fantastic. Thank you, Dr. Lehman. I'll also note the slides are available in the app if you'd like to reference them that way. So I am honored to present our second illustrious speaker, Dr. Brent Forrester, who is the chief of the Division of Geriatric Psychiatry and the director of the Geriatric Psychiatry Research Program at McLean Hospital. He's senior medical director for value-based care solutions and population health management at Mass. General Brigham and an associate professor of psychiatry at Harvard Medical School. Dr. Forrester is an expert in geriatric psychiatry, specializing in the treatment of older adults with depression, bipolar disorder, and behavioral complications of Alzheimer's disease and related dementias. He's immediate past president of the American Association for Geriatric Psychiatry and a distinguished fellow of the American Psychiatric Association. His research focuses on studying novel treatment interventions to manage behavioral complications of dementia, such as agitation and aggression. And he also leads a Mass. General Brigham system-wide initiative to enhance the assessment and treatment of individuals with dementia while supporting family caregivers in primary care settings. So I'm sure you'll agree he's a perfect speaker to lead us into the next section of our talk. Thanks everybody for being here this morning. Thanks to my colleague, Dr. Lehman, for just a fabulous talk and lead into this part of today's discussion, which is really going to be focused on, number one, the biological aspects of Alzheimer's disease in terms of early diagnosis, the use of biomarkers. I want to focus on some of the upcoming disease modifying therapeutics, ongoing trials, and how we've been thinking about their potential use in clinical practice. And then very importantly to all of us in psychiatry is how to manage and assess the common and disabling behavioral symptoms of dementia. So Susan already mentioned this, but I think it's a really important point to keep in mind as we go through this part of the talk, which is that the symptoms of dementia, or MCI, if they're, let's say, present in a 70-year-old, it's likely that the Alzheimer's pathology of amyloid plaques and neurofibrillary tangles began to develop in the brain up to two decades before the onset of symptoms. That's somewhat sobering to think about, actually. So as you can see in this curve, there are two different curves here. Dr. Lehman talked about normal aging, that's the cognitive aging, and some of the associated symptoms she talked about, that's the top line, that's the dark line, and then there's the dotted line below that, which is the trajectory of people who are headed towards dementia. Again, remember, dementia MCI are clinical syndromes, they're not pathological entities, and we're trying to really make that distinction right now. But I want to highlight these three different phases of the spectrum towards dementia as we think about biomarkers and treatments. So preclinical are people who actually have no symptoms whatsoever, no memory loss, no functional impairment, but they have the disease of Alzheimer's in their brain. And again, that can occur up to 20 years before the onset of symptoms. As the disease proliferates in the brain, starts disrupting circuitry and other neurobiological processes, then we start to see symptoms develop. And Dr. Lehman really did a nice job highlighting what MCI is versus dementia, I won't go over that. But essentially, the way I think of MCI is cognitive impairment without substantial functional decline, and then further progression from there to dementia, which is functional impairment plus cognitive decline. And if it's the Alzheimer's type of MCI, in other words, the memory loss caused by the Alzheimer's plaques and tangles or associated with the Alzheimer's plaques and tangles, those individuals convert to dementia somewhere around 12 to 15% of people with MCI will convert to dementia per year. Most individuals, but not all, will then convert over five years. Almost all will have converted to dementia. So in terms of further thinking about biomarkers here, you know, when would you as a clinician, after doing the clinical assessment that Dr. Lehman talked about, even think about doing neuroimaging? And one thing I just want to highlight that Susan mentioned, which I think is the most important part of this talk, if you don't take anything else away from this talk, what I want you to take away is we have a lot of fancy diagnostic tests that are available now, and many more will be coming our way. But the single most important tool that we have is a clinical history. And that clinical history really needs to be gathered not just from the patient and observing the signs that Susan talked about, but also a careful interview with a caregiver or a friend or some collateral information. That often guides you more than anything else that we can do biologically. But when would you do imaging? So the American Academy of Neurology recommends that we do at least one neuroimaging exam during the process of working somebody up for dementia. That could be a brain CT scan or an MRI scan. The MRI scans can sometimes be more helpful in distinguishing hippocampal atrophy, which is associated with Alzheimer's disease. But again, we do not use brain scans, MRI or CT, to diagnose Alzheimer's disease or other dementias. We use them predominantly to rule out other conditions that could be masquerading as a neurocognitive disorder or causing the neurocognitive disorder, like a stroke or a tumor or traumatic brain injury and so forth. But if you see patients who have focal neurological symptoms, tremor, rigidity, gait disturbance, any focal neurological findings, that would be another reason to think about it sooner rather than later. I'm going to talk a bit now about PET scans, so positron emission tomography scans, which are not widely used in clinical practice. If an individual presents early or they have subtle symptoms, or if you're trying to differentiate especially between Alzheimer's disease and frontotemporal dementia clinically, actually Medicare will pay, now for over a decade, they will pay for an FDG PET scan to differentiate between Alzheimer's disease and frontotemporal dementia because it really varies. I mean, the difference is important from a prognostic standpoint. So that might be when you think about an FDG PET. So I'm going to show you a few pictures here. So on this slide on the top, the top two rows are from individuals with Alzheimer's disease and the bottom two are from a normal brain. So what I want you to first look at are the glucose scans, which are the FDG PET, looking at brain metabolic activity and glucose utilization. So I don't know if I have a pointer, but in any case, as you can see over on the glucose scan on the bottom, it's lit up in red. That's active metabolic activity, glucose utilization. That's a healthy, normal brain. But if you go to the glucose scan, which is the FDG PET on the top, that second line that says glucose, the red is gone. It's hypometabolic. And that's really what we see in Alzheimer's disease. And we see it in the temporal and parietal regions. So we see temporal, parietal, hypometabolism in Alzheimer's disease, sometimes years before we see the onset of clinical symptoms. Now about a decade plus ago, probably 2006, was the first time we saw reports of the Pittsburgh compound B, which was the first tracer to target amyloid in the brain so that we could actually see and visualize amyloid. And without an autopsy or brain biopsy, we could actually visualize the pathology of Alzheimer's disease in a human being in a PET scanner. And so what you can see in a normal brain, which is the amyloid scan on the bottom, it's purple, there's no yellow, there's no red. And then if you go to the top, you can see it lit up. And so this is the amyloid plaque deposition that we can see in an amyloid PET scan. So this technology has been around for a while. There are at least three tracers that are commercially available. You could pay for this. Medicare and no other insurance company will pay for a clinical amyloid PET scan today in 2022. But they are available in certain centers, and they cost anywhere between $5,000 plus if you wanted to pay for it out of pocket. And the question you would have to ask yourself is, why would you want to know this? Because unless you have a disease-modifying therapy that clears amyloid and has an impact on clinical symptoms, knowing it may not change course of illness. Making the diagnosis clinically, as Dr. Layman talked about, is critical. But it's still not clear how useful this is clinically. But in research, it's absolutely vital. And we're going to talk more about why this might become more important with the advent of these disease-modifying therapies. So again, amyloid PET scan useful in research, but not in clinical routine care today. So now let me talk a little bit about genetics. The genetics of Alzheimer's disease are complicated. There are two sort of key genetic messages I may want to leave with you, let's say. So the most common allele that's associated with higher risk for Alzheimer's-type dementia is the ApoE4 allele. You inherit one copy of each allele from your parents. And so the ApoE2, 3, and 4 are the three different types of copies that one can inherit. If you inherit one or more, one or two copies of the ApoE4 allele from one or more, one or both of your parents, then you have a higher degree of risk for Alzheimer's disease. But it's not a determinant gene. There are many individuals with Alzheimer's-type dementia and amyloid in their brain who do not have the ApoE4 allele. And then there are some people who the reverse is true as well. So in clinical practice, in a memory clinic, in a specialty memory clinic, we will not collect ApoE4 genetic testing unless it's part of a research study. Because as part of a research study, it might be very important in terms of establishing diagnosis for clinical trials. And as I'll talk about in a minute with adjucanumab, it may actually be helpful in risk for some of the side effects that we see with these disease-modifying therapies. Then there's the autosomal dominant genes, which are, unlike ApoE4, determinant genes. So these genes are rare. I mean, they occur in small numbers of families clustered around the world. One of the most common families you may have heard about is the Colombian cohort in South America. These individuals inherit one copy of these genes from either parent, APP, presenilin 1 or 2, and they definitively will develop the syndrome of dementia and likely at a very early age. The earliest patient that I saw, the youngest patient ever on our inpatient unit at McLean, this goes back 15-plus years ago, was 32 years old. She had already had four children. She was part of a family from central Massachusetts that was known to have one of these genes, and she was never willing or interested in being tested. What's really important about these genes is that it has a window into the concept of doing preclinical interventions. Because if you have an individual, say, in their 30s who has APP or presenilin or one of these mutations, and you know in 5, 6, 7 years, based on the family history, when the clinical symptoms will begin, you could intervene with drugs to reduce the buildup of plaque in the brain or perhaps anti-Tau antibodies. That might be a way to do preclinical intervention. There are numerous studies going on right now to test this sort of proof of concept. So that's about biomarkers. Oh, you know what's not on the slide? I'll just go back for a minute. There are two other kinds of biomarkers I just want to mention because they are going to be probably discussed more with the advent of these disease-modifying therapies. Those are CSF biomarkers and plasma biomarkers. So in terms of the CSF, there are three established, well-known biomarkers in the CSF that are looked for and sometimes used as an auxiliary diagnostic tool. That's CSF markers of Abeta-142, Total-Tau, and Phospho-Tau. And sometimes these biomarkers are altered, Abeta-42 goes down and Tau goes up, in individuals before the onset of symptoms. We can actually bring people into clinical trials now based on their CSF biomarkers alone. And because of the widespread availability of CSF, the relatively low cost, compared to amyloid PET imaging, they may become more commonplace. But what we really need is a serum plasma biomarker. And there's one that looks very promising. It's a Phospho-Tau serum biomarker, which is now being developed. And it looks to be highly correlated with the buildup of amyloid and Tau in the brain and with the course of illness and also the response to treatment with some of these disease-modifying therapies. So keep an ear out for Phospho-Tau serum biomarker or Phospho-Tau because this one is likely going to be available for clinical use and prediction sometime in the next three to five years. But we shall see. So what do we have in terms of treatments today in 2022? What are the goals of treatments for Alzheimer's disease? And where are we headed with research? That will be the next part of the talk. So the cholinesterase inhibitors were first approved with Tacron or Cognex in 1993. It's almost 30 years ago. It's amazing. And they've, unfortunately, I mean, they've been used widely. But I think a lot of physicians, especially those of you who don't practice a lot of dementia have a bit of therapeutic nihilism about these drugs, like, well, what's the point? They don't do much, you know? And if you look at patients over time on these medications as an individual patient, it's really hard to notice. The original studies that were done with the three most widely used drugs now, denepazil, ravastigmine, and galantamine, all of those medications demonstrated benefit versus placebo over six months. And the primary outcome measure was called the ADAS-COG. It's a 70-point scale. And the drug-placebo difference was about four points. It's hard to notice that clinically. But if you follow people over time, those drug-placebo differences are maintained. And if you stop the drugs, you lose the benefit. And sometimes you lose the benefit pretty quickly. And so that's really important because these are not disease-modifying therapies. They don't change the course of illness. They change the symptoms. And they're really working on a very late-stage phenomenon. They're not reducing plaque retangles in the brain. They're basically altering brain biochemistry, which is elevating cholinergic neurotransmission. The kind of outcomes that we're looking for are slowing, gradual slowing of cognitive and functional decline. They may have beneficial effect on behavioral symptoms. And there have been some really interesting analyses that have been published over the years that have shown that cholinesterase inhibitors may help two behavioral symptoms in particular, behavioral and psychological symptoms. One is apathy. And the other is visual hallucinations. So Dr. Lehman talked about Lewy body dementia, individuals presenting with Parkinsonism, visual hallucinations, waxing and waning of cognition. You give an individual like that an antipsychotic medication, almost all of them will get more confused, delirious, fall, become more unsteady on their gait. You really want to try to avoid that. Cholinesterase inhibitors, however, may actually be quite helpful and may be a way to reduce those disturbing visual hallucinations, not acutely, but over the course of a few months. I always educate family, care partners, and patients that this is not a cure, that you should not expect a cure, but you should see a slowing of the decline. And there may be improvements in quality of life. So just to go over some of the medications, there's actually a new one on the block that will be available this fall, which is a derivative of Dinepazil. It's actually a different delivery method. So right now, Dinepazil, which came out in 96, took over the marketplace when it came out because unlike Tacrin or Cognex, it was given once a day. Tacrin or Cognex had liver toxicity associated with it, lots of GI side effects, was not very practical to use. So Dinepazil, once a day, the starting dose of five milligrams a day is the therapeutic dose. Ten milligrams a day is the average dose that most people get titrated to after another month or six weeks. And it's given orally. And some people develop gastrointestinal side effects. So there's a new patch version of this, Adlarity, I believe is the name of it. And it was approved by the FDA in March. And it's going to be available this fall. And it's a once a week patch. Interesting delivery method. I have no idea what the cost will be or if the cost benefit risk will be worth it or not. Razidine or galantamine and rivastigmine are the three cholinesterase inhibitors. As you'll notice, Dinepazil has been approved for all stages of dementia. So some people will say, well, they're too impaired. Why bother? Both memantine, which is a different type of drug which works on the glutamatergic system, and Dinepazil are approved all the way through the severe stages of dementia. Other than the last one on the list, which is namzaric, or just really a combination medication of Dinepazil and memantine, the last approved drug in the United States until last June with aducanumab was memantine nearly 20 years ago. So there's been tremendous amount of trials, which we'll talk about more, with these disease modifying therapies with no success. So there's a huge need for advances in this area. So the next slide has a lot more detail about these three commonly used cholinesterase inhibitors. Again, as Art said, these are available for you. There is a 23 milligram dose of Dinepazil. I tend not to, I'm curious if Dr. Lehman uses it, I rarely will push it that high because of gastrointestinal side effects. Bradycardia is another concern with all of the cholinesterase inhibitors, so that's something to watch out for. But the distinguishing features across the three, which I would have said that until I just learned in the last week or so about this Dinepazil patch, but rivastigmine does come in a patch. I would highly prefer using the patch version of rivastigmine to the oral version just because of the GI tolerability. Rivastigmine oral is really challenging in terms of gastrointestinal side effects, nausea, vomiting, and loose stools, but the patch is really well tolerated. And rivastigmine is the only one of the three cholinesterase inhibitors approved for something other than the Alzheimer's type of dementia. It's also approved for Parkinson's dementia, and it likely has excellent effects in Lewy body dementia. The starting dose of Dinepazil 5 is therapeutic, 10 is the average dose. The starting dose of rivastigmine orally, which you wouldn't use, is 1.5 twice a day. But the patch is 4.6 per 24 hours, and then after a month to go to 9.5. Both the 9.5 and the 13.3 versions of the patch of Exelon are therapeutic doses. So you can see the half-lives, et cetera, and drug interactions are usually not something we worry about a tremendous amount. But I would say the gastrointestinal side effects and bradycardia are the two things to watch out for. If you give these medicines at night, they may cause bad dreams and sleep disturbance. So I generally tend to dose them in the morning with food. So here are the side effects that I talked about, GI, bradycardia, et cetera. Again, maybe because of these drug interactions, if someone has known liver disease, that's a concern in terms of dosing. And then the dropout rate in clinical trials varied between very low and about one-third of patients, depending on the studies that you looked at. When memantine came out, again, it's a different mechanism of action. It's basically blocking the glutamatergic neurotransmission at the NMDA receptor. Unlike the cholinesterase inhibitors, it's renally excreted. So if you had an individual with known renal failure, you'd want to use a lower dose. But again, these are all drug interactions in the liver, and it's not hepatically metabolized much. When this drug first came out, the recommendation was to go up by five milligrams a day every week. So you go five milligrams a day for a week, and then eventually, after four weeks, get up to 10 milligrams twice a day. Some of us noticed that if you do this with this weekly titration, some people get a little too activated and agitated and anxious. And I don't know if this is anecdotal. I don't know if I've ever seen it reported in the literature. It's pretty common. So I now have practiced going up by five milligrams every two weeks. It seems to be helpful. There's no rush. Usually we will prescribe Aricep first and get them on a stable or Exelon or whatever it may be for get them on a stable dose over a period of a few months, and then add Memantine. And the standard of care in 2022 is really the combination of the two together works better than either one alone in terms of slowing decline. There is an extended release version of Nomenda, which goes up to 28 milligrams a day, although I'm not sure it's terribly more advantageous clinically than the 20 milligram dose. All right. So let's talk about disease-modifying therapy. So those drugs that I just mentioned are on the market. They've been on the market now for almost 30 years. And they work on neurotransmission later stage in the illness. The idea behind disease-modifying therapeutics is to try to attack the underlying biology of the neurofibrillary tangles, but especially the amyloid plaques. That's really where most of the research has been done, and either to reduce the buildup or enhance the breakdown of amyloid in the brain. And most of these mechanisms are immunotherapies. So these are monoclonal antibodies that target directly the amyloid in the brain. There are also anti-Tau antibodies as well that are in phase two trials. And you can see, again, the buildup of Tau and amyloid with PET imaging. So let me tell you the story about aducanumab. Unfortunately, we've seen way too much of this in the media in the last year. Dr. Olson, in the background, is one of my colleagues at McLean. We've been doing studies on disease-modifying therapeutics at McLean Hospital for over a decade. We started working with aducanumab after the first trial was finished, and that was the phase 1B trial. This was about 200 patients. It was published in 2015. And actually, the slide on the right is from the Nature paper that showed that this drug actually clears amyloid from the brain beautifully in a dose-dependent fashion. So if you look on the left, it's baseline. The red is amyloid, again, amyloid PET imaging, and the right is a year later. And the top group are placebo. You go on placebo, you have amyloid in your brain a year later. But if you're on 3, 6, or 10 milligrams of aducanumab given intravenously through an infusion once a month, you have a dramatic reduction in the buildup of amyloid in the brain. And no one questions this finding. This is a definitive finding. It's been shown over and again. Not the only drug that can do this. The real question is, does it matter from a clinical standpoint? That's really the question here, and that's where all the controversies come in. So we have a biomarker in the brain. We know it's associated with a clinical syndrome of dementia. We know we can remove it. I mean, we have high cholesterol. We know that statins reduce cholesterol. The reason why they're on the market and everyone takes them is because it reduces the risk of heart disease and stroke. It has a clinical benefit that's pretty clear, or else they never would have been used to the degree they are now. But there are a lot of things in medicine where we have biological targets, where we can definitively improve the, you know, say, cancer-related targets, for example, but not really impact mortality much or quality of life that much. So that's really the question is, can removing amyloid in the brain actually have a clinical effect? And so that's where the confusion comes. So when Biogen did this study, they got very excited by the finding because there was an association with the clinical finding as well. And so the FDA allowed them to advance beyond phase 1B right to phase 3. And they designed two identical phase 3 trials, each with about 1,500 participants. They recruited patients from all over the world. We were one of the sites at McLean. And let's see what the next one is. So these are the two studies. The primary outcome measure is something called the clinical dementia rating scale sum of boxes. It's essentially a composite score of cognition and functioning. And it's a helpful tool. We don't use it widely in clinical practice. A lot of memory centers use it to track and stage dementia. So it's not a singular measure of cognition. It's not a singular measure of functioning. It's not a behavioral measure. It's really a composite functional and cognitive measure. This was the first trial. It was called the eMERGE trial. This is the one that we were involved in at McLean. What happened with this study was they had had a pre-specified interim analysis. All these big studies always do. Because you don't want to go all the way to the end of the study if two things might happen. Number one, there might be a safety problem. And number two, you might want to be careful if the drug is wildly effective. You might want to stop it early so that you don't expose people too long to placebo. So they had a planned interim analysis. One of the couple things that you need to know about these studies, the first one was to get into the study, you had to meet extremely narrow inclusion criteria. These individuals had to have either mild cognitive impairment or very mild Alzheimer's disease. The kinds of people that have been in the trial that Dr. Olson and I have been following for years, most of them, many of them were still working at the time they came in the trial at very high-level jobs, executives of their own companies, teaching at major institutions, academic institutions, and in between infusions were going to teach or going to work. And that's really the kind of person that we're talking about who may benefit, not the people with moderate disease like Dr. Lehman was talking about who come into the office who aren't paying their bills and not driving well. So that's one thing, really narrow inclusion criteria cognitively and functionally. The second thing is they had to have evidence in their brain of brain amyloid deposition, either on an amyloid PET scan or the CSF analysis. The third thing that's really important clinically about these drugs is that because of the mechanism of action of these immunotherapies, they lead to inflammation in the brain. And they basically lead to two conditions, one's called ARIA-E, which is, ARIA stands for amyloid-related imaging abnormalities, these white spots that show up in the brain. They can either reflect swelling, edema, or hemorrhage. So 40% of people in these two phase three trials develop ARIA in the brain, and yet a very small percentage of those have symptoms associated with these neuroimaging findings. But that's one of the concerns. So anyone who's on an anticoagulant therapy, warfarin, heparin, any anticoagulant that you would need to take, say, for AFib or prevent clots, cannot be a candidate for these drugs. And that's still the case. Some of the newer ones, maybe that'll be less of an issue, but for this one, for sure. So this was the positive study. What happened was, in 2019, in March, they stopped the studies, because when they combined the data from the two trials, which was their pre-specified outcome, there was no difference in the CDR sum of boxes. So they killed the drug, they stopped the study. All of our patients were devastated, frankly. They came out of the study. And then about, that was in March. So in September, we started hearing word that, we still hadn't heard what had happened, why they stopped the study, that they were going to proceed, they were going to go further, and they were going to actually resume looking at the data, and they were actually going to try to put people back on drug, and go to the FDA for trying to get approval. And we found out later that when they looked at the two studies separately, they actually saw that this study, let's call it study number one, which is study number 302, but this study was a positive study. It removed amyloid from the brain, and if you looked at the CDR sum of boxes, there was a drug placebo difference. This is low-dose and high-dose on the study, but there was a drug placebo difference for the eMERGE study for 302 in all of these measures, frankly, and there was, again, a much better effect of the 10 milligrams per day than the low-dose of three, but not for this study. This study had no findings clinically. And so they went to the FDA, they had an advisory panel meeting in the fall of 2020, and they basically, the advisory panel basically said to the FDA, you know, you've got one positive study, you've got one negative study, we know it removes amyloid from the brain, there's not enough data to support approving based on clinical outcome. And then last June, 7th of 2021, the FDA approved the drug and put it on the market. And one of the questions was, well, how did they do that, and why did they do that? And they went against their FDA advisory panel. Well, they made the decision, although they hadn't really told the world they were going to make their decision based on this. They made their decision based on its biomarker outcome. Clearly removed amyloid from the brain. We put it through this accelerated approval process. this is the mechanism by which we approve the drug, it's likely in their judgment and the judgment of the field that amyloid is related to the clinical syndrome of dementia so by removing it there's likely going to be an effect. That was the rationale the FDA used to approve the drug in June. I think the reason why there was such a medium maelstrom around this was number one, three of the FDA advisors quit because they were misled in terms of how they were approving the drug. I think the second thing is the cost of the drug was extraordinarily high, it was $56,000 a year for again monthly infusions which could go on for years. And then I think there was all this controversy about what really happened. So that was June of 2021, we're now almost a year in and basically what's happened since then is the center for Medicare and Medicaid services last month in April decided that they would not pay for this drug. And the only circumstance in which they would pay for this drug is if somebody enrolled in a clinical trial. So Biogen has gone back now and they've designed a third, let's call it the tiebreaker study, the third phase three tiebreaker study, it's called Envision, we're going to be a site for that. We're going through the start up right now and that will likely start enrolling subjects later this spring into the summer. It'll probably take three plus years to see an outcome from that study. In the meanwhile CMS is not going to pay for it until then. A couple of our colleagues started to prescribe it because before the definitive CMS decision there was definitely the ability to prescribe it. Some pharmacy and therapeutics committees, frankly most have not put it on the formulary. My personal clinical opinion is that if you catch this disease early and you find the exact right patients and you do it in a very careful situation with experts who understand how to follow and monitor these brain findings, for some people it actually may make a difference. For the people that we have in the trial it could be just a selection bias, but they've been in the trial for now four or five years, they've been back on drug because they're now in an open label part of the study, and they're remarkably stable. Now maybe they would have been remarkably stable without the drug but there does seem to be an effect and most of these folks do not, all of the folks that we've been treating do not want to stop. All right, we can do some more questions at the end. So just a few words now about behavioral symptoms of dementia because a lot of the primary outcomes of those studies I just said are cognitive and functional, but we all know as psychiatrists and those of us who have lived with loved ones with dementia that the real problem with this illness is agitation, aggression, depression, psychosis. It's the behavioral symptoms of dementia that drive the burden of the illness. And there are a couple of issues with this syndrome of behavioral symptoms of dementia. There are many definitions. If you look in the literature, they're all over the place and I think that confuses people. So like Dilip Jesty and Sandy Finkel coined the term the psychosis of Alzheimer's disease. There's the neuropsychiatric symptoms of dementia. There's the one most commonly used in the literature today is the BPSD or the behavioral and psychological symptoms of dementia. But these include a whole host of symptoms. These are symptoms. They're not etiologies. They're not neuropathologies. They're symptoms. It's kind of like the rest of psychiatry in a way, but we've got to figure out what's causing them. That's really our job. So it can include everything from wandering and pacing and worrying to physical aggression and violence, hallucinations, delusions, and mood symptoms. These are common. They're almost universal. In any individual with dementia, they will exhibit over the course of their illness one or more of these symptoms. And when they occur, they're associated with the burden of the illness, caregiver burnout and depression, risk and premature placement into long-term care settings. And overall, morbidity and mortality goes up. And again, the symptoms vary. I talked about the range of symptoms. What I don't have a slide on is that over the course of Alzheimer's disease, you can see different symptoms in different stages. Apathy and depression are more common early on, hallucinations, delusions, agitation in the moderate and more beyond stages, and aggression, again, moderate and advanced. Now, despite the prevalence of these symptoms, despite the fact that they are the most disabling part of the illness, we still have no drugs approved by the FDA to treat the behavioral and psychological symptoms of dementia. There are a couple reasons for that. Number one is, what is it that we're trying to treat here? And that's one of the questions the FDA has asked. And the second is the risk of side effects. And we'll talk about that in a minute with the antipsychotics. Most importantly is the evaluation of these symptoms. Like Dr. Lehman talked about with the evaluation of dementia, when people with dementia develop these symptoms, we got to figure out why. Because until we figure out why, we are totally lost. And you can see patients on three, four medications because desperately trying to do something. But oftentimes, we need to take a step back and figure out what's really going on here. So the three buckets of things that often drive these behavioral symptoms are on the slide, environmental, medical, or psychiatric. And the way I think about it is the environmental precipitance may be the most important in some cases. It could be an exhausted, overwhelmed spouse caregiver whose loved one is asking them questions over and over and over again. And after a while, they become irritable. And they start to fight with one another. Or it could be in a long-term care setting where they're sundowning towards the afternoon. Just at the time nurses have a change of shift and there's a lot of commotion and chaos. It could be the way a caregiver bathes someone. There may be any number of environmental precipitants. But we've got to figure out what they are and address them. Then there may be medical causes. So pain, constipation, electrolyte disturbance, UTI. You name it. Medication side effects, drugs of abuse like alcohol. All of these may contribute to behavioral symptoms. So again, somebody develops hallucinations with agitation. You give them Olanzapine or Risperidone to keep them calm because they're aggressive. But you know Olanzapine doesn't treat a urinary tract infection. You've got to find the UTI that may be causing it. And during the COVID pandemic, we have seen so many older adults with dementia develop behavioral symptoms of dementia, superimposed delirium, hallucinations, agitation as the first sign of COVID-19. And that was often something we saw in the spring of 2020 in particular when we didn't have widely available diagnostic tests. Finally, psychiatric. The reason I mention this is that it's really important, and Dr. Lehman went over this, in the history, is to find out if these individuals had a preexisting history of a psychiatric illness. And I'll give you a very extreme example of this. So I had a patient many years ago and one of the first jobs I had after my fellowship, it was doing some consultations in nursing homes. And I was asked to see this woman in a long-term care facility in a locked dementia unit. And the reason I was asked to see her is because she was not cooperating with ADL care. She was not participating in activities. She was not eating and drinking. And she had just been in the hospital for a medical problem. She had syncope. She had passed out at home. She went to the hospital. So I went to see her. She's standing in the hallway. The first thing I noticed is she's 30 years younger than everybody there. She's in her mid-50s. The second thing was she had no facial expression. She was completely mute. And when I did a brief neurological examination and I shook her hand, she left it up like this. I'm like, huh, that's strange. You've seen catalepsy, you know, waxy flexibility. Anyway, I looked in her chart. There's no history of a psychiatric illness whatsoever. So I called her husband. Like you said, Dr. Lehman, collateral information. What's going on with your wife? And he said, well, we've been married 30 years. We have three kids. She's had bipolar disorder since as long as I've known her. And about three weeks ago, I noticed she was getting quiet and not talking and apathetic. And I thought she was just getting depressed. But she stopped eating and drinking. And one day, she got dizzy and passed out. And I brought her to the hospital. And they tell me she's got frontotemporal dementia, Pick's disease, a rare variant of frontotemporal dementia based on an MRI scan that showed frontal atrophy and a woman who had a mini mental of zero because she was catatonic. And so I said, you know, this may be catatonia. It's a severe manifestation. Sometimes a bipolar illness. We got her hospitalized. She had ECT. And she became my outpatient for the next five years. I learned so much from this patient. I learned so much about the fact that what you see in a medical record, not that it's wrong, but it's incomplete. It is just assume it's always incomplete. And sometimes it's wrong. And you just need to get more information from other people. Second thing is don't be afraid to reassess and rediagnose. And sometimes people will use little, you know, it's like the elephant thing. You see the tail and somebody sees the trunk and you're just, you know, so you've got to really think about the whole person and the whole picture. And here the key was the prior psychiatric history. The other thing I learned was when people are severely depressed or manic or psychotic, you really have no idea what their baseline cognitive status is. It's very hard for them to pay attention to the basic cognitive assessment. All right. So those are the three buckets of things that drive behavioral symptoms. Helen Kales and colleagues, and she's speaking later in this meeting, developed the DICE approach. And it's hard to read this slide. But basically everything I just said has been sort of worked into a beautiful paradigm algorithm of describing the symptoms, investigating the cause, coming up with a treatment plan and evaluating the outcome. And it's just a very helpful tool, trying to find ways to digitize this and to scale it so that it can be used routinely in clinical settings. So I'm not going to go through the details, but I just went over a lot of it just now. So briefly, a few slides on non-pharmacological interventions. If you read all the guidelines, including the most recent APA guidelines from 2016 on managing psychosis and Alzheimer's disease, you will see that always start with non-pharmacological behavioral interventions. Good dementia care is holistic care. If all of the studies that have looked at what will keep our brain healthy with aging and what's good for people with dementia, exercise may have the best data. So keeping people actively, not only physically healthy, but active with exercise. And it doesn't have to be running 10 miles a day, it can be walking, it can be any type of aerobic or strength training exercises, et cetera. Managing the mental health aspects, which we talked about, paying attention to sleep, et cetera, social support, and very importantly, supporting the caregiver. Whether it's in a long-term care facility with frontline CNAs or whether it's at home with spouse or adult children caregivers, caring for the caregiver is a huge part of non-pharmacological interventions for dementia. And structure is so important. I mean, constantly we get questions from families. Should I bring mom on this trip? Should I move mom into a long-term care facility? We do know that the lack of structure is problematic and that changes in routine can be concerning. But it's really important to pay attention to all of these basics on the slides. All of these things can enhance well-being, quality of life, reduce agitation. Keeping people stimulated cognitively, physically, emotionally through various interventions can help. The problem is with all of this, the data to support any one intervention is not terribly great. I mean, there have been some good interventions that have looked at physical exercise, but they're relatively small studies. And I'm talking about interventions to reduce behavioral symptoms. But what's most important is coming up with an individualized plan for the person. And this takes time. It's not as simple as prescribing a pill. This is where staffing ratios and long-term care facilities come into play. This is why I think there's been explosion of memory care facilities throughout the United States and the assisted living level of care, because they address all of these things in some ways better than nursing homes, because it's a self-pay endeavor. There's a lot of education of caregivers that are critical, skill teaching, resilience building in caregivers. It's very hard in the moment to realize when you're getting pestered with the same questions repetitively not to get frustrated, that it's not willful behavior, not to take it personally. Oftentimes the family member will say to us, this is what's happening. They come in the office. They look awesome. It's kind of like with your kids when they go to school and they're like great at school and they're like a nightmare at home. They take it out on you because they know you and there's emotional relationships. That doesn't go away necessarily. Last point I just want to make on this slide, which is so great, which is that just because the person can't remember your visit doesn't mean it wasn't without value. Last week I was at an Alzheimer's fundraiser in Boston and Governor Charlie Baker in our state gave a beautiful presentation. He's a real advocate and champion for Alzheimer's disease research and care. His mom had Alzheimer's disease. One day he was visiting his mom and she didn't recognize him and he was getting frustrated and he was bummed out and he told his dad and he said, dad, I don't know why I visit anymore. She doesn't know me. And he goes, Charlie, it doesn't matter if she doesn't recognize you, but you know who she is and that's what really matters. And of course he starts to break up and cry and he's really amazing at talking about the impact it's had on him and his family, but this is really, really important. I'll just say one other thing. When I first started working with patients with dementia, one of the hardest things was how do you assess somebody who can't communicate with you? How do you assess someone who doesn't know you from day to day, from visit to visit? It can be very hard. A, you can't take it personally. B, I think it's just important to use our clinical observational skills, our curiosity, our, you know, almost like we're detectives to try to figure out what's going on, but the nature of the relationship is really about the moment and it's really not about us. It's about them and what their world is like at the time. So briefly on pharmacotherapy, the conventional antipsychotics work, but they're problematic in terms of tolerability. And that is EPS, extrapyramidal side effects, gait disturbance, et cetera, akathisia, and the tardive dyskinesia risks. Their risks for tardive dyskinesia go up with age and they're certainly higher in women than men, but if you look at this age statistic, it's pretty remarkable. If you give somebody who's 30 haloperidol for a year, their risk of TD is about 5%. Now that person's 65 and it's 28% after a year, and after two years it's 50% and two thirds of people on conventional antipsychotics over the age of 65 will have tardive dyskinesia. This is the main reason why these are not used. There's also a question whether the mortality risk with the conventional agents may actually be greater than with the atypicals. These are the four atypicals on the top that have actually been studied in Alzheimer's disease. When I ask trainees this question in the talk that I give every month for the past, I don't even know how many years, Dr. Lehman, but I always ask, are there any studies to look at the side effects and efficacy of antipsychotics and dementia? They're like, no, probably not. There's a lot of studies. There's over 20 trials with over 5,000 patients. The warning that I'm about to show you from the FDA that came out 17 years ago is because they had a ton of data for meta-analysis. Quetiapine was the first drug to be studied for this. Back in the late 90s, 1999, it was published. Now if you look at the dosing ranges, you'll notice that it's relatively low and lower than you would use, say, for acute mania in a 30-year-old or schizophrenia in a young person. Quetiapine has a big range, as we know. This drug is confusing to dose, especially in older people. The one well-done quetiapine study showed that it took 200 milligrams a day to reduce agitation and psychomotor restlessness in people with dementia. Aripiprazole, there were three studies in dementia that were already done before this drug ever came on the market for what it was indicated for in schizophrenia bipolar disorder and treatment-resistant depression, and the dose range is 5 to 10 milligrams a day. Now there are many other atypicals that have since come which don't have sufficient data. One thing I will alert you to is pimivansirine, which is a, let's call it a novel antipsychotic medication. It's approved for the psychosis of Parkinson's disease. This medication actually went through a phase two trial that was positive, a phase three trial that had a whole slew of types of dementias, not just Alzheimer's. It was positive. It was rejected by the FDA in April of last year, about a year ago. But they went back, the pharmaceutical company went back to the FDA, and the FDA is now reviewing their data, and this summer we're going to find out whether or not they indeed will approve it. Now this is not for dementia-related psychosis broadly, for psychosis related to Alzheimer's disease specifically. So they're going to look at the Alzheimer's data from their trials on which to base a decision for approval. If this drug gets approved, which will be announced on August 4th, I believe, this summer, it could be the first drug approved ever for any psychiatric symptom in dementia, so we shall see. Now look at the TD rates with risperidone and lanzapine. They're not zero, right? They look more like the conventional antipsychotic rates you would see in a young person with schizophrenia. It's about 5% a year. So it's important to monitor for tardive dyskinesia when using atypicals in people with dementia. The problem is side effects, and so the first hint of this came out in 2003 when one of the Janssen-funded risperidone trials showed a risk of stroke-like events, about two to three times higher in drug versus placebo, and if you look at this analysis of all the data for cerebrovascular adverse events, this could be big strokes, small strokes, hemorrhagic, embolic, really pooled it all together. You see that with risperidone, lanzapine, and aripiprazole, there's a two to three-fold increased risk of stroke-like events. Now these are people who have been in long-term care facilities, mini-mentals in the single digits to low teens. These are very impaired patients, lots of medical comorbidity. Not all of them had Alzheimer's-type dementia. Some had vascular dementia to begin with. But quetiapine, weirdly, and again, a smaller N, so maybe not sure what to make of it, had a lower rate, maybe not statistically lower rate, of stroke-like events than placebo. The real problem came out with this warning by the FDA in 2005, and that's really what changed, really was the game-changer, which was that when the FDA did this meta-analysis on 17 trials looking at the risk of stroke-like events, and really this was the look at stroke-like events and death, but they found a death risk difference in people on drug versus placebo. About one and a half times, 1.6 to 1.7 times higher. Some people would say, well, why were people dying? And so we don't know for sure, but the most common listed causes were cardiac, usually sudden cardiac death, arrhythmia, or infectious from sedation and aspiration pneumonia. I know, I'm going to go quick. Look at the APA guidelines. The most important thing to remember is everything I said about how to assess behavioral symptoms, non-pharmacological interventions, and when you need to use these drugs, you can use them with consent when patients present with agitation and psychosis is all in here, as well as an attempt to taper and discontinue after four months. So again, don't overreact. Always look at the underlying causes. And the one thing I will just mention is that these drugs are highly regulated in only one environment, and that is in nursing homes, where there's tremendous federal oversight of the use of psychiatric drugs broadly, not just antipsychotics, and really, really impacts clinical practice. There is some data that antidepressants helped agitation and dementia, specifically citalopram in the CITAD study. The use of these drugs, though, for depression and dementia is more questionable in terms of outcome. Last thing is, there's a lot we can do to promote healthy brain aging, and there's a beautiful report from the Lancet Commission in 2017. Up to a third or more of all dementias may be preventable. These are the risk factors in various stages of life. If you just look at these risk factors, one thing you'll notice is that almost all the things that we know cause heart disease and stroke can also cause Alzheimer's disease, like smoking and diabetes and hypertension and hyperlipidemia, obesity. And here are some recommendations. There's a lot of information out there. I think the Alzheimer's Association may be the single best go-to resource for your families, your patients, in terms of education, knowledge, opportunities for involvement in clinical trials. We have a dementia care consultation program. So to summarize all of this, as general psychiatrists, please look for people with memory loss. Do the evaluation and the thoughtful assessment of patient and caregiver that Dr. Lehman talked about. Know that there are treatments, and think about how best to maximize quality of life by reducing behavioral symptoms of dementia and caring for family members. There will be new therapies on the market that will be coming that will likely improve quality of life. And I'm going to stop there, and we should just take a few questions. Yeah. Sounds good. Well, that was absolutely fantastic. We'll switch over to questions, and we're just going to dive right in. We'll stick around a little past 930 to take your questions. So go ahead, please. Hello. Just a short question. Thank you for your talk. In Norway, clozapine is approved and used for psychosis and Parkinson's disease. Do you have any comments on that? Yeah. So certainly, the use of clozapine for psychosis and Parkinson's disease is something that's utilized here in the United States as well. There have been... I've had experiences using clozapine in patients with refractory psychosis and agitation and Alzheimer's disease. There's very limited data on that. The concern is anticholinergic effects, orthostatic hypotension, of course, the usual agranulocytosis. But it's probably, if you think about an algorithm, it's down the pathway of something we would think about, but certainly not unheard of. We might try quetiapine first, just because it doesn't require the level of monitoring. But yeah, definitely, it's used in this country as well. We're going to alternate front and back, so go ahead. Hi. I just wanted to know if you could talk about the environmental exposures of benzodiazepines. I know high-dose benzos chronically, but anticholinergics, even low-dose benzos, if we're way over-medicating all these patients that we have at younger ages, what can you tell us about the status of that? Yeah. It's an interesting thing about benzodiazepines, and thank you for bringing it up, because actually the prescription of benzodiazepines goes up with age. And we know that older adults, and particularly even those over the age of 80, and women more than men, are most likely to be on chronic, long-standing benzodiazepines. Most of those prescriptions are not done by us. Most of them are done by primary care physicians who keep people on long-term benzodiazepines and usually not for a psychiatric diagnosis anymore. They just reflexively keep prescribing, re-prescribing, and reauthorizing the prescription. So there's a lot of interest in, and we really need to be taking more of a careful view ourselves as psychiatrists of ways to be able to help our colleagues. There's actually an interest now in what's called de-prescribing and helping them. You just can't stop at long-term benzodiazepines, right? We know about the withdrawal that can happen, and sometimes that happens if someone gets hospitalized for another medical problem. So we have actually an annual geriatric conference in Baltimore every year. I actually was working, gave a talk just this March with a pharmacist on helping general clinicians and geriatricians on how to de-prescribe benzodiazepines because there's a lot of issues related to memory over time that can happen and falls and confusion, that sort of thing. So thank you, great point. Speaking to the FDA-approved medications that we've had, I've seen two different kind of thought processes. One is if they can tolerate it and there's not a problem, just keep using them because maybe they're getting some benefit. The other is if we can de-prescribe and de-complicate their medications, that if it's not really helping, you're not seeing a big difference, go ahead and get those out of the system. So I'm just curious as to what y'all think about what the long-term plan is for those meds. Yeah, so it's a really great question. I'm not sure there's a single answer to that. I think in every single case, think about the individual patient that you've got in front of you and don't just use broad strokes. But this is the way I think about it. With the cholinesterase inhibitors, it's pretty clear. If you stop those drugs, even if you taper them, there's a pretty rapid decline back to where they would have been months and months ago before they ever went on the drug over a very short period of time. It may even be a withdrawal syndrome. It's hard to know. Maybe it's cholinergic. It's really not clear exactly what that is. So I've gotten, in my mind, following the mantra, if they're tolerating the medication well, they're agreeing to stay on the medication, it's not causing significant problems, then unless there's no function worth preserving, and that, again, is an individual decision based on the patient. And the reason this happens is because I've seen patients who are in long-term care facilities with mini-mentals that are very low because they've got language disturbances, but they're still walking to the cafeteria, they're feeding themselves, et cetera, they're cooperative with ADL care, you stop the drug, no longer so, and they're not delirious from something else. It's from stopping the drug. There was function worth preserving in that situation. Again, many of these are also approved into the advanced stages of illness. Memantine may be less associated with this withdrawal phenomenon than the cholinesterase inhibitors. This is a clinical sort of anecdotal experience. But that's the way I think of it. If there's function worth preserving, we continue, and if not, then it may be time to stop. Great, we'll go back. So speaking of memantine, you mentioned that if titrated too quickly, it can cause activating behavior. But what about once the patient shows signs of agitation? How do you feel about continuing memantine? Do you wanna say something first? Yeah, I mean, in that case, I probably would be less likely to think that memantine was a contributor to the agitation and would be thinking, as Brent shared with you, what else is going on? Is there something, a change in the routine? Has there been a caregiver change in the household? Is there something more disruptive that's causing an element of stress? Is there something else going on biologically? Constipation, which all of our older patients make people uncomfortable, it often goes along, we know, with depression. You can't imagine how often just something like that could be a cause of agitation in someone. So I would be unlikely to be thinking at that point if they were stable it was memantine, but would be thinking about what might be other causes, environmental or biologic. Thank you. Go ahead. Thank you first for two wonderful presentations. I was wondering about how much important could be the early diagnosis of dementia, considering that actually we cannot change the course of the disease and if all the social aspects we could include since the beginning. So how much do you think we should emphasize the early diagnosis and why is it so important? So I'll start with that. So I think it's critical for many reasons. One reason is it's really important for families and patients to be educated about what this is and what may be coming next. Therapeutic or diagnostic disclosure is not an easy thing to do. And in some ways, the way we treat Alzheimer's disease in 2022 is the way we treated cancer in the 1970s or 80s. What we have said back then when we didn't have great therapies, should we even bother making the diagnosis? Well, some people didn't want to even tell the patients they had cancer and now it's the same thing in Alzheimer's disease. So I think we got to move past that. So the reasons to make the diagnosis earlier is to engage the patient and their family in the journey of dementia. It's gonna be a journey, it could take years and it's gonna impact all aspects of their life and it's gonna massively impact their families. And then the most important reason is because there's a lot we can do for people with dementia. And I think this is where the therapeutic nihilism and ageism bias is problematic. Instead of thinking about making a diagnosis, see you later, I'm sorry, you've got this terrible illness, it's more about how can we improve your quality of life? How can we keep you safe? Those two key things, right? And then all that flows from that. The opportunity to involve yourself in a clinical trial that might actually have benefit, but at a minimum will get you connected to a regular caregiver team has a hugely profound impact on folks and their families. So I think all of, those are just some of the reasons why I think making the diagnosis early is critical. It will also influence other medical decisions about how aggressive to be about certain interventions, what other medications you should or should not be on. So that's a quick answer. I probably should keep going. Yeah, so I just wanna quickly add to that. I mean, I agree with everything that Brent just said in answer to that question, how important it is. But I also think this is why we as psychiatrists need to be involved. Because to be honest, what often happens with my patients, they might come to me after they've had a diagnosis of dementia made by the neurologist who made the diagnosis and says, come back in a year. Come back in a year. You know, the patient has a myriad of questions. They're anxious, they're fearful, they're concerned, they're worried. I think it's really important for us to be able to say, you're the same person today you were yesterday. Change is gradual. And to also keep in mind, there have been a number of studies that have come out recently showing that within three to six months after a new diagnosis of MCI, mild cognitive impairment, or dementia, there's an increased risk for suicide. Okay, this is huge. I'm so worried about this. Because we just can't easily just make a diagnosis without follow-up and without seeing people and telling them, this is a partnership. I'm there with you. You're the same person you were the day before. Change is gradual. Let's focus on what's still there. Let's help you prepare for the future and keep wise about it, but be able to continue to support you. John, I'm back. It's often said, as alluded in your talks, too, that depression is a harbinger. In late onset, depression is a harbinger of dementia. On the other hand, we see some depressed people, somewhat resistant depression over years, 30 years, 40 years, suddenly going to a cognitive decline. Are there any ways that without any cognitive deficits, we could somehow premonition of sorts that these people are going to go through the cognitive decline later? Yeah, so it's very interesting. People are very interested about what's the life trajectory of depression. You probably remember that we used to believe that midlife depression was a risk factor for later dementia. We certainly know that when older patients develop a serious clinical depression, they very often have cognitive impairment, but the impairment they have that's associated with depression is executive dysfunction. It's really not short-term memory impairment. It's not a problem of forgetting like Alzheimer's is. My older patients who are depressed, I really want to support them with executive functioning, which may mean they have difficulty cooking, they have difficulty managing their finances and things like that, but when they get better, that will all be remediated and they'll be a lot better. It does seem to be that a lot of those early studies, like it was the Framingham Heart Study that really was done early on that seemed to suggest that people who had midlife depression were later more depressed, but those individuals weren't followed so much as well as some of the more later studies have been. So midlife depression itself can cause cognitive deficits, but it's probably not a risk factor per se for late life depression, unless you have people who have treatment-resistant depression and don't get fully well. And we see those individuals too who just never go back to full functioning. And for those individuals, we just want to keep trying to treat their depression and help them. One other point I'll just make just from a biomarker standpoint, there was a trial that was completed a few years ago called the IDEAS trial. And in that trial, those of us considered to be dementia experts around the country were enrolling patients who had a differential diagnosis of this might be Alzheimer's disease, or maybe it's something else. That was really the question. And so on all of those people, they had an amyloid PET scan. And the real question that the investigators were trying to answer is if you knew someone's amyloid biomarker status, did it matter in terms of diagnosis or treatment? So because we're at a psychiatric hospital in McLean, a lot of our patients had chronic and severe mental illness, bipolar disorder, depression. They were now presenting with cognitive concerns. They may have been very treatment refractory. And now all of a sudden we had an amyloid biomarker or not. And it made a huge difference in terms of how we thought about their prognosis and their approach to care. So when we have more readily available biomarkers that reflect brain neuropathology, I do think especially when we have treatments that may actually address that, I think it really is gonna impact the way we think about what treatment resistant depression in an older person really is. Yeah, go ahead. Thank you for your presentations. Do you have any experience in the combination of antipsychotic medication in dementia and cognitive enhancers, particularly the cholinesterase inhibitors, having increased risk of extrapyramidal side effects and tardive dyskinesia? Yeah, so are you, so the combination of the two together, so it's an interesting question. I mean, I don't usually think of the cholinesterase inhibitors further exacerbating extrapyramidal side effects. I usually think of that coming from the antipsychotic medications. The most important thing that your point raises to me is that in geriatric psychopharmacology 101, do one thing at a time so that you know what's going on. Never prescribe two medications at the same time because you'll always get confused. And the second is less is more, right? So sometimes we do wanna deprescribe as you were talking about, because sometimes the symptoms that we're seeing, they could be neurological, they could be psychiatric or cognitive, that they're being caused by the medicines we're giving patients. So I think more often than not, Susan and I probably take patients off medications than we put people on medications for all of those reasons. That's the first appointment, is look at the medication list and see what can come off that doesn't need to be here. Thank you. Go ahead. I have two questions. The first one is a kind of straightforward question. It's been many years since I've done geriatric psychiatry, but I remember one of my supervisors used Depakote like crazy for agitation and dementia. Is there any role nowadays for anticonvulsants? And my second question is more theoretical. My very biased, limited anecdotal experience is the people with insight into their dementia seem to be the ones who are very well educated and high functioning, and less so in people less educated. I'm sure it was a biased view. I'm just curious if you have any thoughts on that. I'll take the first one, you take the second one. Okay. Although I have opinions on the second one, it's interesting. So I too, 20 years ago, was using a lot of DIVOP ProEx for agitation and aggression and dementia. And then five studies were published and not a single one of them demonstrated an improvement in whatever the primary outcome measure was. One of the studies looked at secondary mania, one of them looked at agitation, et cetera. Some of them didn't even show benefit on the secondary outcomes. And then there are the problems with gait disturbance, liver toxicity, drug interactions, and so forth. And frankly, delirium from hypermonemia. So I've personally tended to use, I still see it being used occasionally, but probably less DIVOP ProEx. However, the idea of using anticonvulsants that may be less toxic to the brain or have drug interactions is not a bad idea. And so some of us, Dev Devanand is leading the charge from Columbia, and I'm one of the participants in a discussion about a potential clinical trial with gabapentin. So for years, after the problems with Depakote, why not use gabapentin? And frankly, clinically, I use it quite often in agitation and anxiety and Alzheimer's disease, but there's literally no data. There's some open label anecdotal case reports, and that's about it. But it doesn't have the same problem with drug interactions. It's renally excreted. It doesn't have the clearance through the liver problem. And it doesn't seem to cause delirium at relatively low doses of between three, 600 milligrams a day, let's say. So I do think it's worth further study, but there's really not definitive evidence. And there's almost no evidence with the other anticonvulsants, unfortunately. And then I'm just gonna add just to remind you that we have no FDA-approved medication for agitation and dementia. And this is such a huge problem for families, which is, you know, it's the number one reason probably why families decide somebody needs to be in a nursing home because they can't manage them at home anymore. So it's a huge problem. There is no FDA-approved medication, which is why we often turn to medicines we have familiarity with in other kinds of contexts because the families need it, quite frankly, and the patients need it. In terms of insight, it's very interesting. I'm not aware of any studies on this. So I'm gonna just speak from my own anecdotal experience. And I gave you the example during my talk of someone who was very well-educated and aware of her dementia. I will tell you, I've also recently seen a Hopkins faculty member, somebody pretty well-educated. And his department was very worried about his cognitive impairment that was affecting his teaching with the fellows and his teaching in the clinic. And he had no awareness of his cognitive deficits and his dementia. And he was very unhappy with the recommendations that he needed to be changing what he was doing. So I've seen it. It's shocking to see that, actually, when individuals who seem to be so well-educated don't appreciate it. And yet I just, dementia affects not only specific domains of functioning, but how you put the world together. How you assess and understand things that make sense of the world. So in that way, it's understandable. Yeah, I agree with everything Susan said. Let me just say one other thing. First of all, I would remove that bias from your mind because I do think it's another one of these biases that sometimes we hold onto. I just saw a world-famous professor who had no idea how cognitively impaired he was. And he was still functioning because, and this is the other key thing with dementia, if dementia's affecting some specific cognitive domain that does not impact someone's social graces, their ability to understand verbal communication or to speak, then if something is really well-learned and routine, even if it's a very high level for most of the public, but routine for that person, you'll have no idea they have a problem. So this person was going around giving international lectures and doing consulting, and no one really knew there was that much of a problem, except for the people with him day in and day out and saw what was going on around the house. Next. Thank you so much. This is an outstanding presentation. The best so far I have attended. Oh, thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. My first question is, do you have any comments about use of medicinal cannabis in BPST? I come from Australia, so that's why I don't want to say that it's recommended here. You already answered that question. So is there any role of medicinal cannabis, TSC CBD, in BPST? So I'll answer that one. So we have a NIA-funded clinical trial looking at dronabinol, which is synthetic THC, to treat agitation in individuals with Alzheimer's disease. We've recruited 60 of the 80 people in the trial so far. It was based on pilot data that we started accumulating in the mid-2000s, open-label use of this drug, 10 milligrams a day on average, is where we're going for a dose of 10 milligrams a day. Tolerability is so far excellent. Again, we don't know who's on drug and placebo, but dropouts have been minimal, and we'll just wait to see the outcome of that trial. Dr. Krista Langtote, who's from Canada, published a study with Nabalone, which is another synthetic THC, which was a positive trial. So there is data to support the efficacy of synthetic THC. When you talk about medical cannabis, something you might buy at a dispenser, you get prescribed by a physician, you have no idea what's in it. You really have no idea what's in it. There are other constituents beyond THC and CBD that may have psychoactive effects, they may have side effects, they may have drug interactions. So I think the word is, again, it's really complicated territory. CBD, okay, which might be safer, may be less likely to make agitation worse or cause psychosis, there's so limited trials because of federal regulation in our country that makes it so hard to study. We are doing a study right now of a plant-based cannabidiol product, not funded by industry or anything, it's a philanthropic funded study. It's a 12 patient study with mild Alzheimer's disease with a 96% CBD compound with just a teeny bit of THC. It's a liquid preparation given twice a day and it's an eight week study and our primary outcome is anxiety. So there's gonna be some data, it's gonna be modest and I think the world of what people are doing with regards to medical cannabis clinically, I mean, like personally, is way beyond anything we can ever be able to study, unfortunately because of regulation, et cetera. All right, so I'm just gonna add to this just to differentiate for you. This could be a whole nother hour talk, to be honest. We did this at AGP, by the way, this year. So if you're interested in that talk, it was an hour and a half. But what Brent is talking about, just I wanna be sure that it's really clear. These are pharmaceutical preparations that he's studying. Okay, they're pharmaceutical, right? Your nabinol and nabalone. Why is that important? Because they're standardized. We know what the doses are, we know who is making them, we know how they're prepared and they're still studying it. So it's too soon to know. When patients come to you, like they come to me all the time, every week I have a patient who says they wanna go get cannabis from the dispensary, their sister said they should do it, their friend said that they should do it. We don't know what those products are. There's no standardization, there's no oversight by the FDA. We don't know what the products are, we don't know what's in them, there's no way to compare us, there's no standard of comparison. My patients tell me, oh, it's a natural product, it can only be helpful, it can't be harmful. Remember back to Goodman and Gilman, my textbook of medical school, right? What did you learn in, I'll learn this in our pharmacology course, all drugs are poisons. Everything has the potential to cause a negative effect. Everything does. And no one, I tell them, no one has done the study of this product in you and you have 20 medical problems and you're on 15 other medications. We don't know. Anything you take could make you worse. It's not that it could only make you better. So I'm very, very cautious. I'm excited about the studies that are being done with pharmaceutical preparations to see what we can learn from it. Take one last question. Thank you. Hi. I work as a psychiatrist in a primary care setting as the only one. And I just kind of wanted to double check, I think you said this in your talk, if I do a thorough history, get some basic labs, do a MOCA, is it okay to stop there, make a diagnosis of Alzheimer's type dementia as the most likely start of medication? I get kind of confused if I go to update date and it says CSF, you can do these imaging, is without imaging or any further workup, is that still standard of care? So I would say, you could probably say I'm very concerned that what you have is a probable diagnosis. I think what we need to do in geriatrics though actually, which isn't done enough, is collaborate. I think what I would want to do and what I do is reach out to the primary care physician and talk to them. Not just send them a copy of my note and talk, I have a concern about this, here's what I've done, is there anything else that you want to do? Let's talk to each other. Because it's really a team effort to take care of the patient and that person is involved also. They need to know what your worries are and there may be other things that they may want to do. They might at that point want to refer to a neurologist and I'm okay with that. If that happens, they want to get somebody in to bring another opinion because these diagnosis, there's not hard and fast, you're going to see how people do over time. But I think we don't need to do it alone. We made it sound like the psychiatrist here is carrying the whole burden and we do a lot of the work. But maybe a parting thought is not only to reach out to family but to reach out to the other important physicians who are caring for the patient. And just one other thing, this afternoon at 1.30 p.m. there is a talk on novel models of geriatric care in primary care settings and this issue will be addressed. Yeah, great. Well I want to thank all of you. I mean it's just amazing you stayed 20 minutes past the end. The level of interest so high. Thank you Dr. Layman, thank you Dr. Forster. And I'll say if you want more, if you want a deeper dive into behavioral and psychological symptoms of dementia, come back at 10.30 for what will be another fantastic talk. So thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you.

memory complaints

older adults

Alzheimer's disease

dementia

early recognition

comprehensive assessment

current treatments

cognitive decline

biomarkers

disease-modifying therapies

non-pharmacological interventions

behavioral symptoms

management

research

education and support