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 | Science in the Cinema 2008 Transcript: Away From Her |
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National Institutes of Health
Science in the Cinema 2008—Away from Her
Post-Film Discussion—Neil Buckholtz, Ph.D.
Dr. Fuchs: Our speaker this evening is going to be Dr. Neil Buckholtz. Dr. Buckholtz is chief of the Dementias of Aging Branch, in the Division of Neuroscience at the National Institute on Aging, at the National Institutes of Health.
Dr. Buckholtz holds a doctorate in physiological psychology from the University of Wisconsin at Madison. He was a faculty member at the Medical University of South Carolina, in the Department of Psychiatry, from 1970 to 1983, before he came to the NIH.
His current position involves overall programmatic responsibility for the development, coordination, and implementation of both basic and clinical Alzheimer’s disease research; specifically, the diagnosis, treatment, and management of Alzheimer’s disease.
So, please help me welcome Dr. Buckholtz.
Dr. Buckholtz: Good evening. Just for your information, the reason that I’m wearing a uniform is that I’m in the Public Health Service Commission Corp and this is our uniform.
We’ve all seen a very wonderful movie this evening that deals with a very difficult subject of how Alzheimer’s disease progresses and the effects that it has on family members and other people.
The central irony for me, in the film, is that Grant didn’t want to be away from Fiona. But through the progression of the disease, she went away from him. And so what this shows us is that as the disease progresses, the individual who has Alzheimer’s disease loses his or her personhood, and the disease takes that person away from us.
What I would like to do is talk for just a few minutes about what to me are the three stages of the film and some of the lessons that we can take away about how our understanding of Alzheimer’s disease is affected by how the disease progresses from the mild to the moderate to the more severe stages.
In the first third of the film, when Fiona is at home, you can see that she recognizes what’s happening to her. She uses the yellow stickies to remind her about where things are. She says, “I may be beginning to disappear.” And yet, there are fluctuating levels of memory. Sometimes her memory is very good. Other times it isn’t. Sometimes she remembers things and facts. She remembers the plant. And yet, she goes to pick up the bottle of wine, and she doesn’t recognize the word “wine.”
Another interesting aspect, and Grant mentions this: she seems very young. Most people who have Alzheimer’s disease get it in their seventies and eighties. And yet, what we’re seeing today, what seems to be happening, is that we see people who are beginning to get Alzheimer’s disease, what we call the late-onset Alzheimer’s disease (that’s distinguished from the more strictly genetic form, which is called early-onset Alzheimer’s disease) in their fifties and sixties. We really don’t understand if that’s an aspect of better diagnosis, people being more aware of the disease, or exactly what’s happening. But it’s a phenomenon that seems to be occurring.
The other thing I want to mention about this earlier stage—and as she progresses into the more moderate stage—is what’s happening. There are not just memory changes. We often think of Alzheimer’s disease as a memory disorder. It is a memory disorder, but there are other kinds of behavior symptoms that are going on at the same time. The one that you saw in the film is wandering. People very often wander away from their home. They don’t know where they are. You read in the papers all the time that someone with Alzheimer’s disease has disappeared and they’re trying to find that person.
There are other behavioral symptoms that were not shown in the film and are very important and that you should know about because they are a distinct part of the disease. Things like sleep disorders, hallucinations, delusions, depression, and agitation. These behavioral symptoms are very difficult for family members to deal with. They are very often the reason family members make the decision to put their loved ones in a care facility.
Another aspect in this first third that was shown a couple of times is the aspect of home safety. As you remember, Grant has to turn off the stove because Fiona has forgotten to do this. So these are very important aspects of the mild and more moderate stages.
I think the thing that seems the most atypical to me of anything in the film that really doesn’t strike true in terms of what we know about Alzheimer’s disease is that it was really Fiona who decided to take the lead in going into this care facility. That’s something that doesn’t usually happen. As I said, most often what happens is that the family members simply cannot deal anymore with the sleep disorders, with being up all night, dealing with aggression, the agitation, trying to manage the individual in the home, and they finally have to make the very difficult decision to put the person in a care facility.
So then what you see is a transition into Meadowlake. And again, Fiona’s memory declines even further. Yet, she’s still aware of what’s going on. She says, “It’s not all gone. It’s going.” As you saw again, her long-term memory seems to be pretty intact. It’s the short-term memory and the fluctuations in short-term memory and the decline that’s indicative more of this moderate stage of disease. Then what happens is that Fiona becomes very attached to Aubrey. Again, this is not something we usually consider, and yet, you know that in the news was former Supreme Court Justice Sandra Day O’Conner’s husband, who developed the same sort of attachment to someone in the care facility where he was placed. So it is not that unusual, but it obviously affects Grant a lot.
Grant has been in denial for a lot of this. He said, “Well, she’s not going to the second floor, she’s only going in for a short period of time.” This is something that really affects Grant a lot. So he says, “What are you doing with Aubrey?” And she says, “He doesn’t confuse me.” She’s trying to simplify her life. She doesn’t understand all the complexity that occurs when Grant comes to visit. And so, it’s much more comfortable for her, for her involvement with Aubrey, than the confrontations that happen when Grant comes to visit.
Finally, there is the transition to the dreaded second floor that Grant really did not want to happen. This represents, I think, the inevitable progression of Alzheimer’s disease. Sometimes it tapers off, sometimes it reaches a plateau. But inevitably, it declines. That decline can take a period of time. It may take three to five years. It may take fifteen years, depending on the individual. But the person never comes back. That’s really something that we are trying hard to deal with.
We’re trying, through research, to delay the progression of the disease and eventually to delay its onset and prevent it entirely. There’s a tremendous amount of research that’s going on. We have to do a lot more. There are a lot of frustrations that occur. And yet, there are still things, even at this later stage of the disease that we can do for people who have Alzheimer’s disease to make their lives easier. Fiona says, “Read to me. Make me feel better.” A caregiver can still do things. There are still things in the environment that can help.
Interestingly, I was at a wedding very recently in Macon, Georgia. My nephew got married. His mother-in-law, who’s in her early sixties, has Alzheimer’s disease. She was very involved with music in Macon. Her husband was the manager of Otis Redding. They played a lot of music at the reception, and she got up and she was dancing and singing. And so, these kinds of things come back for a period of time. And those provide comfort to the individual and also help in terms of the interactions of that individual with the environment.
So the message that I would like to leave with you, before we get into the question-and-answer session, is that there is a lot of research going on. There’s better understanding of what happens in the brain as the disease progresses. We know that the disease starts in the brain five, ten, perhaps even fifteen years before symptoms develop. And our hope is that by developing new methods for diagnosing Alzheimer’s at its very earliest stages in the brain before symptoms develop, we will eventually have treatments and have drugs that can delay progression of the disease and delay its onset.
Frankly, it’s been frustrating at times, but I am very optimistic that at some point, we will have these drugs and we will be able to help people who have Alzheimer’s disease and their family members. I do want to point out that in the material you received, there’s information about the National Institute on Aging’s Education and Research Center, through which you can get a lot of information about the disease, about care giving, about drug treatments, and about diagnosis. I also want to mention that another major source of information is the Alzheimer’s Association and their chapters around the country. So with that, I will be happy to take any questions that you have.
Question: I was curious. How realistic or common is it for someone to have the ability that the professional play-by-play announcer had, as well as even discerning Grant’s broken heart?
Dr. Buckholtz: That may be a little too literary. But actually, some motor skills – those kinds of skills – are preserved in Alzheimer’s disease. It’s another kind of memory that’s more preserved than the kinds of memory that we usually think about. So, I think it’s a little overdone, but it’s not absolutely.
Question: What’s the difference between a severe dementia and Alzheimer’s? Someone who has had dementia for ten years but does not manifest the aggression or the disorientation that you mentioned as a symptom?
Dr. Buckholtz: Dementia is a general term. It basically means a decline in intellectual function that affects daily activities. It’s a general umbrella term. There are different kinds of dementias. The most common type of dementia in older people is Alzheimer’s disease. Alzheimer’s disease is a very specific kind of dementia that affects older people. About seventy percent of all dementia in older people is Alzheimer’s disease, followed by frontotemporal dementia, Lewy body dementia, and vascular dementia.
In everyone who has Alzheimer’s disease, you see a memory decline, but not everyone gets all the different kinds of symptoms. There is some variability in that aspect—in terms of the stages of the disease.
Question: You mentioned about the ongoing research. My mother had Alzheimer’s disease, and fourteen years ago she was on Aricept. Today, I still see commercials on television for Aricept. Is there no other drug after that? The other question is tied to the first question. How much has your research funding increased?
Dr. Buckholtz: I may not be able to answer the second question. For the first question, unfortunately, it is true. There are basically four drugs that are in use that have been approved by the Food and Drug Administration. Three of them are like Aricept. They are called cholinesterase inhibitors. They increase the amount of a neurotransmitter in the brain called acetylcholine that is associated with memory. They are not effective for everyone —only a certain proportion of people for a certain period of time. Donepezil and Aricept are approved for all three states of the disease—mild, moderate, and severe.
There is another class of drugs called Memantine that acts through a different mechanism through a different transmitter and has been approved for moderate to severe Alzheimer’s disease. The first drug, Tacrine, was approved in 1992. It is no longer in use. The other drugs were approved in the mid to late 1990s. So far, no other drug has been shown to be effective in Alzheimer’s disease.
Unfortunately, just last week, another drug that was thought to be effective was shown not to be effective in a Phase III clinical trial. So, it has been frustrating. On the other hand, there are many clinical trials that are ongoing right now looking at the various mechanisms of Alzheimer’s disease targeted toward various mechanisms in the brain. And again, I think it’s only a matter of time before one will be shown to be effective. Unfortunately, it has been very frustrating.
With respect to your second question, I can only say that basically for NIH as a whole, funding has been flat for the past three to four years. That is about all I can say.
Question: I wanted to know if it was possible that the thirty-day separation at the beginning of her institutionalization might have caused a more rapid decline.
Dr. Buckholtz: That’s interesting. I have not seen that before. I don’t know how general that is. I do think that’s an interesting point that you bring up. I think the stress of the separation from Aubrey, for example, was obviously a major stressor. I think that was the reason for her subsequent decline.
Question: I think that was my question. So my question to build on is: how typical is a thirty-day total separation in institutionalized care? Do you have an idea?
Dr. Buckholtz: I just don’t know. I’m sorry.
Question: Any suggestions or recommendations in helping a parent, in my case, accept the fact that they have Alzheimer’s? She is on Aricept, but thinks it is for other purposes. Do we just go along with her game and just pretend that it’s just normal symptoms?
Dr. Buckholtz: I think for each family it’s a different dynamic, and you have to figure out the best thing for that individual. What’s the best way to handle that situation for that individual? I don’t know if you’ve developed a relationship with the Alzheimer’s Disease Association chapters in this area, but talking to other people is often very helpful in terms of understanding how other people deal with these kinds of situations. But again, I think it’s the individual family dynamic that’s very difficult—whatever makes it easier for the family and for the individual who has Alzheimer’s disease. I don’t think there is any one right answer.
Question: Dr. Buckholtz, could you please discuss some strategies for prevention or delay of onset of Alzheimer’s disease besides drug therapies?
Dr. Buckholtz: We don’t have any drug therapies right now. What we do know, we know from epidemiological studies or observational studies. These are studies that take relatively large groups of people who don’t have the disease and follow them over time and look at who gets Alzheimer’s disease and who doesn’t. Then we look at the characteristics of those individuals who get the disease versus those who do not.
Some of the things that we understand from these epidemiological studies, for example, are that people who are more physically active are at less risk of developing the disease. People who stay mentally active are at less risk. People who have fewer cardiovascular symptoms, e.g., hypertension, less diabetes, and lower cholesterol, are at less risk of developing the disease. So, those are some of the things that we know.
The problem is that doesn’t prevent you from getting the disease. These are populations of individuals. Those are good things that are good management and that are good things to do anyway, e.g., stay physically and mentally active, watch your weight, and keep your blood pressure low. Those are good things to do, but they are not guarantees that you will never develop the disease. Unfortunately, that is about all we know.
We don’t have any treatments. There have been lots of suggestions with respect to diet. Another thing we know from epidemiological studies is that people who eat more fruits, vegetables, and fish, because of the omega-3 fatty acids presumably in the fish, are at less risk. These are things that you can do that are not terribly difficult that may help you to prevent the disease, but there’s no way to guarantee that you will never develop the disease.
Question: Somewhat related to the last question, I was wondering if you know of comparative research that shows the incident rate of Alzheimer’s is fairly similar between different nations? How does North America compare to other countries? Is there a difference? Are there any theories as to what might cause this differential?
Dr. Buckholtz: There are some populations around the world who seem to have a lower incidence of Alzheimer’s disease. There have been some cross-national studies. For example, a study in Ibadan, Nigeria, shows a lower incidence of Alzheimer’s disease versus a group of African Americans in Indianapolis. It is not clear. It may have something to do with dietary intake. There is also a lower incidence in India. There are not a lot of those studies.
One risk factor that I didn’t mention has to do with genetics. For late-onset Alzheimer’s disease, there is a specific gene for apolipoprotein E4, which is something that affects cholesterol transport. There are three kinds of apolipoprotein alleles: E2, E3, and E4. The E3 is the common form. E4 puts you at higher risk of developing Alzheimer’s disease. E2 puts you at lower risk. So, there are differences, for example, in Ibadan, Nigeria, in the incidence of individuals who have this E4 form.
But again, this is a risk-factor gene. Just because you have the gene doesn’t necessarily mean that you are going to get the disease. It puts you at a higher risk. But there are people who have the E4 form of the gene who don’t have the disease. There are lots of people who don’t have the E4 form who do have the disease. It’s another one of these risk factors that we have to consider. There is no guarantee either way that you’re going to be able to prevent the disease or that your risk is necessarily higher.
Question: Can you talk about genetic inheritance probabilities?
Dr. Buckholtz: Direct family members, i.e., siblings and children, are at higher risk. It’s not exactly clear how much of a higher risk. This particular gene that I mention, this apolipoprotein E4 gene, does put you at a higher risk. The environment also plays a role. So why is it that people who have the E4 form don’t get have the disease? There may be something, some environmental influences, that we don’t yet understand—some dietary influence, for example, that even though you have the gene, you don’t get the disease. There is a genetic component in late-onset Alzheimer’s disease. It does put you at higher risk. But it’s not exactly clear why some people who are at higher risk don’t get the disease.
Question: I have heard that if you think you’re getting Alzheimer’s disease, you’re not. I was wondering if there is any truth to that.
Dr. Buckholtz: Well, you know we talk about “the worried well.” Many of us, as we get older, can’t find specific words and forget where our car is in the parking lot. Those are generally considered to be normal aspects of cognitive aging. Unfortunately, we all show some declines as we get older. But that’s not Alzheimer’s disease. Alzheimer’s disease is a specific deficit in memory that’s demonstrable with formal clinical and neurophysiological testing. There is a difference between normal cognitive aging and Alzheimer’s disease
Alzheimer’s disease is a specific disease. One of the areas of research that’s ongoing now is to try to understand what it is – why some people in their eighties and nineties can go on very well—they maintain their cognition very well—whereas others do not. My mother-in-law is going to be ninety this year. She is as sharp as a tack. She has other physical disabilities, but mentally, she is quite sharp. We are trying to understand why that is and what distinguishes normal brain aging from these other aspects of pathological brain aging.
Question: I guess what I’m more interested in is looking at it the other way. People who do have Alzheimer’s, do they know that they are losing it?
Dr. Buckholtz: Yes. I think that is an important aspect of the film. At least in the early stages, people do know that there is a problem; that they are losing their memory. It’s only in the later stages, the more moderate and severe stages, where they don’t have that understanding anymore.
Question: To what extent does your institute do any research on other kinds of dementia? And if you don’t, for funding reasons, to what extent is the research you are doing on Alzheimer’s helpful in the treatment of other forms?
Dr. Buckholtz: As I mentioned before, there are other kinds of dementia of aging. Frontotemporal dementia is one where the changes in the brain are more in the frontal part of the brain. In Alzheimer’s disease, there are changes in what are called the temporal and parietal lobes in the back of the brain. In frontotemporal dementia, there’s a deficit in the frontal part of the brain as well as the temporal part of the brain.
Very often you see other kinds of symptoms, especially behavioral and personality changes. So there is research going on there. There is something called Lewy body dementia. Another fairly common form of late-onset dementia is vascular dementia, in which they are not large strokes, but small strokes that are called micro-infarcs that produce the dementia. The other thing that I should mention that we are learning from pathological studies is that it’s very common to have all these forms—all the pathological hallmarks in the brains of older people. People can have Alzheimer’s disease, but they also can have these multi-infarcs in the brains. It’s not always easy to distinguish one from the other. What we are learning is that having these small infarcs exacerbates symptoms of Alzheimer’s disease.
Question: If a person’s memory is slowing down, and they’re not quite sure what it is, would you recommend them taking Aricept anyway? Are there any side effects?
Dr. Buckholtz: First of all, what you really need to do is have a workup by a neurologist, a psychiatrist, and a geriatrician to get a good diagnosis because there may be other things producing the dementia. Depression, for example, commonly shows a lot of the same sorts of symptoms as Alzheimer’s disease, as well as some other medical conditions. The physician, in conjunction with the patient and the family, would decide with respect to what kinds of treatments are appropriate for that individual. But the really critical thing is to get a really good diagnosis by an individual who is trained in working with older people.
Question: What is known about the effects of music? In the film, on the second floor, Grant makes the observation that they are obviously not picking their own music. Maybe most of them wouldn’t want to or are not capable of doing that. Yet, obviously, different types of music have different effects. That is known scientifically. In nursing homes, it seems like caregivers often treat the residents like young children. To me, it’s a kind of disrespect. It seems like they don’t treat them with the maturity that they deserve.
Dr. Buckholtz: As I mentioned in the wedding that I was at, the music that was there was very activating. The woman who had Alzheimer’s disease really reacted. It brought back memories for her. There are therapies that involve music. I can’t directly address your question. In general, I think it is very important to look at what the remaining strengths of the individual are. What is retained? Not just what is lost, but what is retained and how can you work with what is retained to keep that individual active. If that individual has been interested in music, or a particular kind of music, that may be a way of doing that.
Question: Doctor, about early onset in the forties and early fifties, what can you share in terms of any sort of causes, genetics or otherwise?
Dr. Buckholtz: Those are definitely genetic. There are three genes that lead to early-onset Alzheimer’s disease. These are different for different family members. In some families, individuals can get Alzheimer’s disease in their thirties. So for these early forms, it’s generally the thirties through the fifties. It’s definitely a Mendelian inheritance. It’s definitely genetic.
There have been studies to try and understand what is going on because the mechanisms in the brain seem to be the same as those in the later-onset form. But why people get the disease at such an early stage is not clear. We are hopefully going to be funding a large study very soon to look at this to try and understand—by using various neuroimaging modalities and by looking at blood in cerebral spinal fluid—how the disease develops in people with the early-onset form of Alzheimer’s disease. It’s a major research issue. I’m hopeful that through the various studies that we are doing, we will be able to understand this. It does basically seem to be the same disease as the people with late-onset Alzheimer’s disease.
Question: Since the symptoms can take about ten to fifteen years to develop, should one take an exam anyway? Have a neurological exam just to see? As part of checkups or something? Or is that too difficult to do?
Dr. Buckholtz: You’re talking about people, just in the normal course of a…
Question: I don’t know if that is practical. Just to make sure you’re not developing the disease?
Dr. Buckholtz: That’s an interesting question. There’s a difference of opinion. General screening, i.e., community screening, is probably not realistic at this point because we simply do not have the methods for screening large numbers of people for Alzheimer’s disease.
If you are in your sixties and you go in for a yearly physical, then some people say that it would make sense to have testing done every year so you can determine if your memory is being maintained and if there are some problems. If there are problems, then you can intervene at an early stage. The problem is that a lot of physicians are not trained to be able to do that. The other thing is that it takes time to do these kinds of exams. As you know, time is getting shorter and shorter for many of us who have our physicals. So there are lots of people who think it s good idea. It has not gotten into general practice yet. But it may in the future, especially if there are easier ways—if there are computer-based methodologies that would allow you to take five or ten minutes where a technician assesses your memory, as they do for an EKG for example. So it is a possibility.
Question: What is the status of using probes to look for physical changes in the brain early on? I know folks are looking for probes that can identify amyloid or other things. What is the status?
Dr. Buckholtz: As I said before, there’s a major research effort going on to try and diagnose Alzheimer’s disease at the very earliest stages of the illness. One of the things that’s being done is looking at various ways of imaging the living brain. I think one of the really major advances over the past ten or fifteen years is the use of magnetic resonance imaging to look at the structure of the living brain and positron emission tomography (PET) to look at the function of the living brain. There are now studies which indicate that even before symptoms develop, there are changes in certain parts of the brain that can be seen using these various imaging modalities.
Over the past five years, a PET method has looked at amyloid in the brains of living people. I think tremendous strides have been made. The other thing to look at is what we call biomarkers—chemicals in the blood or cerebral spinal fluid which will indicate the very earliest changes in the brain. There has been a tremendous amount of work and a lot of success in this area as well. So I absolutely think that we now have methods to look at very early changes. We are developing methodologies to look at this transition from normal aging to dementia. That has actually been a tremendous research success over that past ten years or so.
Dr. Fuchs: Before I ask you to help me thank Dr. Buckholtz for his service tonight, I will invite you to come back next week. Our film will be . It is based on a true story about an editor of the magazine Elle who had a stroke and was only able to communicate by blinking a left eye. This is a popular film. It is a French film that got a lot of notice. The folks at the American Film Institute told me that they have received a lot of calls about this film next week. So, my recommendation to you if you would like to attend next week’s film is to come early, get your ticket, walk around and come back on time so that we are sure to be able to seat you.
Now please join me in thanking Dr. Buckholtz. |
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