Chapters Transcript Video memory and aging test All right. Thanks everyone for joining us. Um, it's an honor to have Doctor Bruce Miller here today with us. He's the professor of neurology and director of the, of our UCSF Memory and Aging Center, um, a leading authority on frontotemporal dementia. Doctor Miller's work has redefined clinical and research approaches to neurodegenerative disease. Uh, today, he'll share insights into the involving signs of dementia, covering biomarkers, typical presentations, and implications for position, precision medicine. So please join me in welcoming Doctor Bruce Miller. Thank you. Thank you. OK, um, Continue to share, yeah, can you see my uh. Screen OK? Yes, we can see your screen. I'm glad to answer questions as I go along. I, I'll end early, so you definitely have time for questions. Um, OK. So, what, what I'm gonna do is give a brief overview of the magnitude of this problem, why so many of you see patients with these, uh, uh, disorders. I'll also touch on the diminishing, uh, prevalence of Alzheimer's disease in high-income countries. Uh, I'll talk about treatable risk factors, uh, the things we can do in our lifestyle that I think about in every patient I see. Uh, a brief overview of diagnosis of the three major degenerative diseases, Alzheimer's, frontotemporal dementia, Parkinsonian dementias, and then, and then talk about this huge explosion in biomarkers that we have that are aiding our ability to diagnose these conditions, uh, before someone gets very sick. And then, uh, talk about current treatments, and then, Treatments that are on the way. Um, so I think that you know these, uh, these numbers, but, uh, dementia arises every 3 seconds across the world. Um, about 3/4 of people with dementia have not received the diagnosis. Um, uh, 80% of the public in the United States are concerned about developing dementia at some point. Uh, but as many as 1 in 4 think there's nothing we can do, and you know, we can do something. Um, about 2/3 of healthcare practitioners across the world incorrectly think that, uh, dementia is part of healthy, normal aging. So there are really two stories that are emerging. One is in low-income countries, where you see this massive increase in the number of people suffering from dementia. Um, some of this is because in low income middle countries, the population is aging. But the other side of it is that risk factors for degenerative diseases are increasing. Obesity is increasing, exposure to pollutants in the air is increasing, lack of treatment for hypertension, um, uh, loneliness, all these risks for dementia are increasing, uh, making it more likely that people from these countries will develop dementia. But look at how flat the curve is for people from uh uh high-income countries like our own. Um, and this is a punchline here about this. I think it says something really important clinically. A Swiss autopsy study, this is a high-income country of 1600 brains showed a significant decline in amyloid between 1976 and 2006. So amyloid, the Alzheimer's protein, is decreasing at each age, people over the age of 50, remarkable, I think. Uh, it says that, you know, the disease is becoming less common as we get older. It's not disappearing, but it's becoming less common. And, and, and, and I'm gonna read this. So, while the number of people with dementia, including AD, is rising across the world because people live longer, In high and middle-income countries, improvement in living conditions, better access to education, improved healthcare are likely to have reduced the risk of dementia later in life, and that's kind of our job, isn't it, in our clinics. It's to make sure that the reversible causes for cognitive impairment are addressed before dementia ever emerges. So what are those treatable risk factors that we're doing something really important about in the United States? This is a Lancet Commission overview, and, and there are more, but these are things that are undoubtedly responsible for somewhere between 30 and 50% of all dementia in the United States. Low education, lack of cognitive stimulation, head trauma. Loss of uh visual or hearing, um, uh, ability to hear, lack of exercise, smoking, um, none of this is surprising to you, but, you know, I, I, I think that more and more in high-income populations like all of us. We're doing something about each and every one of these risk factors, and it's uh not something to, uh, you know, play lightly. This is really important in dementia care. And It's increasingly clear that Alzheimer's disease has vascular components. Also, the risks for vascular disease are similar to the risk for Alzheimer's disease. Dementia is often mixed. Vascular risk factors can be modified, and, uh, control of, uh, cardiovascular risk factors, uh, are beneficial for multiple organ systems. Uh, change in systolic, uh, hypertension in one of your patients is doing something profoundly important. I'll, I'll come back to that in a second. So just a few of the things that I think we must think about in terms of uh uh prevention. The first is that uh sleep disordered breathing is a major risk for death. We all know this, hyperintensities in the white matter of the brain, uh, stroke, heart disease, but also, uh, almost certainly a risk for MCI and dementia. Uh, if you have bad sleep apnea, you have oxygen desaturation, uh, decreased time with a, uh, uh, serum arterial 02 of, uh, greater than 90%. And so, this reduced oxygen supply is a very potent risk for cognitive impairment. Must be treated. Uh, often treating it by itself will improve cognition in your patients. But we also believe you're doing something to stave off dementia as well when you treat sleep apnea. Another different story that is new and really exciting is the story of uh sleep and Alzheimer's disease. So, sleep impacts Alzheimer's pathology. If you don't sleep well, and I'll explain this, you're more likely to get Alzheimer's pathology, and conversely, if you have Alzheimer's pathology in the brain stem in sleep centers, This can affect your breathing, uh, and, and, uh, uh, it can affect your sleep as well. So, um, age-related sleep changes trigger Alzheimer's disease pathology. How does that work? Well, we know that when we get into deep sleep, uh, this is non-REM, non-dream, deep sleep, two things really important happen. One, we consolidate memories. So, if you are not getting into deep sleep, uh, during the course of an evening, you are not going to remember things in the day that you need to remember, uh, as you would if you got into a, a deep sleep pattern. Another thing that happens in deep sleep is we have something called the lymphatic system, which clears the bad Alzheimer proteins, amyloid, tau, um, and that's only active, that system, when we're in non-REM slow sleep. So, if we can get you sleeping better, get you sleeping more time in non-REM sleep, you'll remember better, but you'll also uh be protecting yourself from Alzheimer's disease. We know that for years, we in our, our clinics have been giving people drugs like Valium, uh, any of the benzodiazepines that block deep sleep. So, we're probably putting our patients at risk when we do that. One of the few sleep, uh, aids that we have, trazodone, terrible antidepressant, but really good sleep agent, um, uh, seems to help people, uh, sleep well and also helps them to get into deep sleep. So, that is my preferred medication in my clinic for someone who's got serious trouble with sleeping, who we need to treat, but we don't want to give them a treatment that increases their risk for Alzheimer's. Big believer in the Mediterranean diet, um, general guideline, um, uh, think that people who live, uh, in blue zones where people live to become centenarians. Communal eating, active lifestyle, high adherence to a a diet that uh uh includes lots of fruits, uh, vegetables and seeds, uh, fish over meats is much more likely to uh not develop cognitive impairment with age, and even people who are in the early stages of cognitive impairment. Seem to benefit from a Mediterranean style diet. Um, this is something that we preach to our patients as well. Physical activity is my mantra. Almost any type, moderate intensity, greater than 45 minutes, any frequency, is good for the brain. Uh, we can see changes in memory structures, better, uh, uh, uh, integrity of white matter, brain connections. We've done a study where physical activity is associated with less blood markers of inflammation. And in our super agrs, these are people over the age of 70 who remember like 20-year-olds, almost each and every one of these people were a serious exerciser. So come to the memory and aging clinic center, get directions on how to exercise. Depression is complicated, and I'll, I'll say this briefly, but it, it, it is both a risk factor for dementia and in, in some cases, an early symptom of neurodegeneration. One example, one of our Parkinson's physicians, Andrea Saratin, showed that if you developed late life anxiety or depression, You're much more likely to develop Parkinson's disease. Are you anxious and depressed, causing Parkinson's? Probably not. The time sequence that Andrea showed, it looks like this is an early symptom of Parkinson's disease. So, think about the implications of a late life onset of anxiety and depression, um, but also treat it. And uh here's one study that showed that People who were treated with uh antidepressants, uh, actually uh showed less accumulation of the Alzheimer protein. So it's never, you know, I never take the argument, well, I don't like to take medications. Someone's depressed, they need psychotherapy, and uh if they need an antidepressant, I think we've got really good data to encourage that. OK. And then the last risk factor is, um, particulate in the air, and, um, Pollution increases the risk of cognitive decline by 81% in this recent study, and all dementia by 92%. It's a big risk factor for dementia, and it's particularly bad in people who carry the APOE4 gene, which is the major Alzheimer risk gene. Um, particulate exposure, uh, uh, leads to misfolding of a beta. It causes selective injury to the hippocampus, um, and decreases glutamate receptor within the hippocampus. Uh, so, uh, uh, we can, we can try to get our patients to live in areas that have less pollution, but I think this has social implications as well, um, and I believe in a pollution-free environment very strongly. This is the fingers study that uh started in Finland and has now been translated across the world. Uh, Alzheimer's Association has been really key in instituting this, but what they're doing in countries in Africa, South America, we're starting to get some good results. Uh, the good diet, physical exercise, vascular metabolic monitoring. Decreasing loneliness, some cases, cognitive training. We're starting to see better outcomes, uh, in elderly populations. So, uh, what does that mean, as I talk to you, as, uh, you know, people who work in cognitive clinics, think about these interventions for your patients. I, I think they do a lot of good, and, uh, they're not the only thing, yeah, drugs aren't the only thing that we need to think about. Protect against vascular disease, exercise, participate in social networks, stay mentally active, see your doctor. Those are the modern messages of social determinants of health. OK, just about 4 minutes on one of my favorite topics, which is giving respect to elders. Uh, and, uh, I, I made this slide before I was an elder, so anyways, it's not just self-promoting here. Um, many societies value elders as a unique resource. They have a profound influence on the young. Sarah, I would not have gone to Indianapolis to live with my grandparents if I didn't admire them greatly, and I wouldn't be a physician without them. So, really, really, uh, you know, important in all of our lives. Um, there's strengths that are actually better in elders. These include emotional skills, better at forming social relationships. General happiness is higher in elders despite the emerging health conditions. And I think increased generosity, creativity, and wisdom are present in many of our elders. We want to protect that. Um, here's some, uh, people who did their most important work as elders. Uh, Eugene O'Neill wrote his greatest plays with Parkinson's disease. De Kooning became an even more brilliant artist with Alzheimer's disease. Ravel with progressive non-fluent aphasia wrote Bolero, one of his most important pieces, and you know, you don't see many philanthropists are young. It says something that, you know, about that aging process and, you know, something that we all work to preserve in our, in our clinics, these wonderful aspects of aging. Um, this is a story I've written about, and this is an artist you can hear in the background, Bolero. This is Anne Adams. She was a biologist. She stopped working in 1994 to take care of her son who had had an accident. She became obsessed with bolero, and she, uh, what she did in this piece, she gave each note, her favorite note, uh, a color, and then just captured the, uh, snaking crescendo of this piece, and you're starting to hear it louder and with more volume, and also the rhythmic repetition of this, it repeats over and over again. Um, so, And about 4 years before she developed progressive aphasia, became obsessed with bolero. Uh, Ravel, About 2 years before he developed progressive aphasia, wrote Bolero. So, uh, almost 100 years separating these people, um, uh, both locked into this very unusual piece of music and became a, a, a brilliant artist, uh, even to the point that, uh, when she was close to death, and we were able to discover the physiological explanation for that. So in 1994, when Ann did that really beautiful piece Unraveled. She, uh, developed headaches, so she got an MRI scan. Nothing to do with clinical symptoms. About 4 years before she developed progressive aphasia, her brain showed massive atrophy in Broca's area in the left frontal region on the left side. So, uh, she was, uh, on her way to progressive, uh, aphasia, asymptomatic. And during this period when she was visually obsessed and produced the most beautiful paintings that I've ever seen, the back of Ann's brain, particularly on the right side, the visual side, had increased functional activity and increased volume. It was reshaping itself. Um, is this unique to Anne? No. This happens with all degenerative diseases. Alzheimer's disease starts in the back of the brain here, but you see in the early stages, increased activity, increased volume in these emotional regions. So I, I, I think it's a story that is very interesting in terms of art, but it's also very interesting in terms of the people we're seeing in clinics. They have enormous deficits, but they also have areas of the brain that are working extremely well, so tapping into those brain areas is really important. This is a study I did about this with Adi Friedberg. I'm not gonna go into the details, but. What it showed us is that every patient with frontotemporal dementia that we had an image for, had increased activity in the back part of the brain, the visual cortex. So, the visual cortex was up-regulated, uh, they were more visually curious, they were more visually active, um, but, uh, not all of them became artists, but in the group with the degeneration in the left temporal lobe, Almost 7% became artists, and many more became great gardeners. They developed more visual skills. So, I think normally, the language areas suppress our visual processing, and in the early stages of these degenerative diseases, our patients have enhanced visual ability. Let's tap into that. Let's Work, get them to work with artists. Let's get them to work on um wood projects. Let's get them to tap into the great strengths that are still present. Diagnosis What do we do? First, if we don't ask, we don't know. So ask if there's a problem. Assess with whatever tool you like, whether there's cognitive impairment or not. I get the MOCA when I go to see my doctor every year. So far, I'm doing fine. Evaluate for treatable causes of cognitive impairment, thyroid, B12. Some cases you may want to look for abnormalities in the kidney, um, uh, liver function. Assess uh to determine whether this is just mild cognitive impairment without affecting function, or whether function is impaired and a diagnosis of dementia is more appropriate. Then discuss the diagnosis and then come to a care plan. I think one of the questions that you wanted me to touch on is uh dementia versus delirium. When should you be worried about delirium, and I think, you know, we're always worried. A sudden deterioration in one of the patients that comes to see you, a fever. I think you all know, not all elders make a fever response, but certainly someone in your clinic who's developed a fever and is acutely deteriorated, uh, you have to, uh, assume this is delirium. Fluctuating consciousness, sometimes very alert. Hyper alert, sometimes, uh, lethargic, uh, uh, sleepy. The test that I like to use is digits forward. Almost anyone should get at least five digits forward. Another test I do is raise your hand every time I say the letter A, E, F, A, M, A, and a delirious person is unable to, you know, maintain that alertness, hallucinations, myoclonus. So, though you have seen delirium, you treat it. Um, uh, and most importantly, uh, you look for the cause. So, uh, we all look for urinary tract infection, uh, make sure there's no chest infection. Someone is very sick, we need to look at the spinal fluid. Do routine, routine metabolic work, think about heart failure, medications, uh, could this be seizure. So those are the general things I do when I think about and worry about delirium. Um, mostly you'll be seeing people in your clinics with dementia, um, uh, progressive loss of, uh, cognitive abilities associated with a functional decline. Many causes for dementia, never stop with dementia. You really wanna know the underlying etiology. AD, chronic traumatic encephalopathy, the Parkinsonian dementias or dementia with Lewy bodies. So, dementia is only a a a, a, a larger heading. And this is uh disease progression, and this is the new, new world we live in. It wasn't the way I thought about dementia when I was growing up. So, um, uh, this is the progression, and we think Randy Bateman uh showed me a statistic in familial Alzheimer's disease that the blood biomarker for amyloid turns positive 19 years before someone becomes symptomatic. So, that's why in our clinics, we're doing a lot with the risk factors for cognitive impairment, um, but just remember that this is a very slow process. Uh, the molecules that are slowly accumulating in the brain, around the time someone develops mild cognitive impairment, brain volume is starting to diminish. For some degenerative diseases, neurofilament is elevating. Um, mostly the frontotemporal dementias, and, uh, they're evidence in some diseases of inflammation, but look at that long, long course of disease progression. How do we deal with that story? OK, well, uh, here's my simple table. I think of, um, the first symptom, Alzheimer's, it's usually memory, uh, trouble finding your car, your keys, spatial, sometimes it's more language, word finding, frontotemporal dementia, behavior, behavior, behavior, uh, disinhibition. Uh, addictive behaviors, loss of empathy for loved ones, these are all of the things that patients with frontotemporal dementia. Exhibit before they become severely cognitively impaired. The Parkinsonian dementias have a very different spectrum of presentation. Before you ever see changes in movement, Parkinsonism, you develop sleep disorders, REM behavior. These people act out their dreams during sleep. They develop depression, anxiety disorders that are sometimes very severe, and Unlike anything they experienced earlier in life, sometimes they develop trouble with sexual function, autonomic, and sometimes, uh, trouble maintaining a blood pressure. Uh, so, very different clinical symptoms, uh, when you see these people in the early stages. If you see them in the late stages, all these things merge together, uh, so it becomes much more difficult. But really, I think 80% of people without anything else other than the story, you can make a pretty good diagnosis. MRIs, learn to look at them yourself. Alzheimer's disease, uh, you tend to have diffuse atrophy, but biparietal and medial temporal atrophy. Uh, frontotemporal dementia, it's a frontal presentation. Parkinsonian dementia is, it's a, a, a, a little bit, uh, uh, less precise, um, but tends to be posterior. Different treatments, cholinesterase inhibitors for Alzheimer's and the Parkinsonian dementias. Um, uh, now we have anti-amyloid therapies for, uh, Alzheimer's. Antidepressants is really the best therapy we have for frontotemporal dementia. OK. Just briefly, the pathology of Alzheimer's, uh, we get amyloid beginning in the brain 20 years before someone's symptomatic. So, if you have a patient who you think has Alzheimer's disease and they have no amyloid on the PET scan or on your biomarkers, very unlikely they have Alzheimer's. Um, the tau PET, uh, you know, the abnormalities in tau happen a lot later. Uh, they, uh, happen when someone is beginning to develop symptoms, and they represent abnormally phosphorylated tau. So, this is what Alzheimer's looks like with PET. We have good blood tests for Alzheimer's disease now, uh, and, uh, some of these are now FDA approved. I use them almost every patient I see in my clinic. Um, the two ones that are available now, phosphorylated 217 and 181, not only capture abnormal tau, but they also are a marker for, uh, uh, for, uh, amyloid beta. Um, the better test is probably phosphorylated 217. Um, and, uh, you know, it's, it's, uh, positive in MCI and Alzheimer's disease with dementia. Uh, and so I think it's a real tool for us and a very non-invasive one. Um, this shows, uh, some looks at, uh, phosphorylated tau. Um, it, it strongly correlates with tau PT, so I, I think the, the, the, the test is increasingly used in deciding whether someone has Alzheimer's disease and also whether we want to lower amyloid in the brain. It's a very huge development. I just point out that for a lot of diseases, and we're working on this at UCSF, we, you know, almost none of the frontotemporal dementias have a good biomarker. Um, Alzheimer's disease is often associated with aggregates of a protein called TDP 43. It's called limbic associated, um, uh, traumatic encephalopathy, uh, and, uh, uh, this is something that we can't measure yet. And Parkinson's disease, we're starting to get spinal fluid tests, but we're still a ways away from a really good Parkinson's biomarker. It's coming. Uh, we're working a lot with an AI approach where we will use our pathology proven cases, uh, uh, use, uh, automated analysis of the image, um, and, uh, predict whether someone has AD or frontotemporal dementia or something else. This is coming, and I would guess within 4 or 5 years, all of us will be using AI in some way to aid us in the way that we diagnose people in our clinic. I don't think it's super hard to be precise in diagnosis, but AI will help us. Treatment. OK. Donepezil, don't forget it. In this era when everyone's getting an antibody for amyloid, I just remind you that, uh, uh, you know, that, uh, people who were given placebo in more than 100 cholinesterase inhibitor trials deteriorated significantly over a year. Whereas people who were given donepezil, uh, improved, uh, uh, on average, about 3 mini mental state points, and then by the end of the year came back toward baseline, but the placebo group was continuing to decline across the year. So, very important to think about this for your patients. I wanna be fair to all of them. I confess. Mostly I used donepezil for Alzheimer's. I'm just accustomed to it. Uh, I use. Almost never oral rivastigmine. I think it causes, uh, more nausea and GI upset. Um, I use, uh, uh, rivastigmine patch for the Parkinsonian dementias cause I think the data is better for it. Another to do, not to do, I think data is very good that memantine. Uh, slows progression and sometimes helps with agitation, and it, uh, moderate to severe Alzheimer's disease. It has no use whatsoever in mild, uh, uh, cognitive impairment or early Alzheimer's disease. No data to support its use. So, cholinesterase early, think about Ana memantine in the moderate to severe stages. OK. Treatment of behavior, I just point out it causes significant caregiver stress, endangers the caregiver and the patient, reduces quality of life, leads to accelerated functional decline, um, often leads us to give chemical restraints, which diminish the capacity of the patient to walk, and, you know, we have a black box warning for a lot of the antipsychotics, so I really try to avoid them. My approach to behavior is identify the problem. Is it benign enough, we should do nothing about treating it. Consider caregiver and family as much as the patient. Try environmental intervention guide is now a Medicare approved, um, um, pathway for you that you can use to, uh, involve a care team navigator to help the family cope with the problem. And then the two big questions I ask, above those, uh, uh, are they on too many medications, but is the deficit due to a cholinergic problem or a serotonergic deficit? Antidepressants may be helpful in some patients, cholinesterase and and inhibitors and others, and for the most part, those are my, my uh go-tos in treatment of behavior. The anti-amyloid therapies, uh, are now, um, you know, very successfully being used in many clinics across the United States, Europe, Australia, some in South America. Um, uh, the two ones that we are FDA approved for, for leanumab and denabumab, to show you, you know, these people did a little bit better over 76 weeks than the placebo group. It's not a cure. It's not a miracle, but it slows progression. Leanimab is a monoclonal antibody. It helps your immune system target specific proteins to be removed, in this case, amyloid. It's given intravenously every two weeks. Now you can give it once a month. It doesn't cure Alzheimer's disease. It modestly slows progression. It, only in early. So, um, we only use these medications in people with mild, uh, Alzheimer's disease or mild cognitive impairment who have shown to have amyloid in the brain. Denaumab, same story. Uh, what it shows here are, uh, the way that, uh, patients, um, uh, who are given this antibody clear amyloid from the brain. Um, so this is after 76 weeks, and Uh, dabumab, uh, you know, clears almost all the amyloid in people with Alzheimer's. Why doesn't it cure Alzheimer's disease? Because tau is also incredibly important for the clinical state, and it doesn't remove tau very well. OK. Side effects, uh, this should not be done casually. Um, we have a special board that considers, uh, treatment, uh, headaches, reactions to IV, small microbleeds in the brain. In the big studies, about 4% of participants, 0.4% died. Uh, due to brain hemorrhages, it's not very high. Uh, the rate is much lower at our site because we're careful about who we put into treatment trials. Uh, so if people have small hemorrhages, they don't get this. We're very cautious about APOE 4. Here's what the hemorrhages look like. They can cause, uh, edema, which is called RAAE, and they can show these little black dots, hemorrhages. I look at the MRI of every patient to see whether they have any of these black dots when I wonder about Alzheimer's disease. Future treatments, I'm almost done. Uh, this is a big trial for PSP and Alzheimer's disease led by Adam Boxer at UCSF. Um, and, uh, these are trials across the United States where people are being given amyloid and tau lowering, or tau lowering alone. I'm very excited about these treatments. I think they'll be much more efficacious than amyloid lowering alone. So, get your patients into these trials and stay tuned for results. I think they'll be very exciting. Um, last, uh, last comment, uh, we have a special initiative at UCSF where we're, uh, working with Nobel laureate, David Baker to find better biomarkers for the non-Alzheimer's dementias. The lysosome is where we get rid of bad proteins in the cell. Uh, Amy Gao and Martin Kampman are figuring out ways to modify the lysosome to help it get rid of bad proteins better. Martin Raappe is working in a similar way in the proteosome, and then we're working with our Nobel laureate, Jennifer Doudna, uh, to, uh, use CRISPR to cut out bad genes in people with monogenic causes for dementia. So I think the future is bright. My last comment, dementia is prevalent. We need precision to recognize biological subtypes. Anti-amyloid therapies show mild, mild efficacy. Tau therapies are on their way. Will we need multiple compounds, probably. Are we in the early days? Uh, yes. I don't think we're up the wrong tree, though. I think we're really doing the right thing. So, let, let, let me stop with that and I'm. I, I left some time to take on any questions that you might have. Published Created by
