Amyvid: “Seeing” alzheimer’s for the first time
BACKGROUND: Alzheimer’s is the most common type of dementia that can cause problems with thinking, memory, and behavior. Fifty to eighty percent of dementia cases are patients with Alzheimer’s. The disease progressively gets worse, interfering with daily tasks. The disease is fatal and there is currently not a known cure. Although Alzheimer’s mostly affects people 65 and older, it is not just a disease of old age. Close to four percent (or 200,000) of Americans, with the disease have early onset, also known as younger-onset, which appears when they are in their 40s or 50s. In the early stages of Alzheimer’s, memory loss is mild. However, as the disease progresses it can cause a person to lose their ability to respond to their surroundings and lose their ability to carry on a conversation. Alzheimer’s is the sixth leading cause of death in the United States. On average, people live eight years after their symptoms are noticeable to others. However, survival can range from four to 20 years depending on age and other health concerns. (Source: www.alz.org)
7 STAGES OF ALZHEIMER’S: Not everyone will experience the same symptoms or progress at the same rate. However, Barry Reisberg, MD, clinical director of the New York University School of Medicine’s Silberstein Aging and Dementia Research Center, created a 7 stage framework for the disease:
· Stage 1: No impairment. The person does not have any memory problems
· Stage 2: Very mild cognitive decline. Person may feel as if they have memory lapses, but can’t be detected by an exam.
· Stage 3: Mild Cognitive decline. Family, friends, and co-workers begin to notice difficulties like remembering names, the right word, losing valuable objects, trouble organizing, etc.
· Stage 4: Moderate Cognitive decline (early-stage Alzheimer’s). Medical interview should be able to detect it. Symptoms include: forgetfulness of recent events, impaired ability to perform challenging mental arithmetic, forgetfulness about one’s own personal history, moody, and greater difficulty performing daily tasks.
· Stage 5: Moderately severe cognitive decline. Gaps in memory and thinking are noticeable and they begin to need help with day-to-day activities. At this stage, they will not be able to recall their own address; they are confused about what day it is; and they need help choosing clothes.
· Stage 6: Severe cognitive decline. Memory continues to get worse, personality changes get worse, and they need extensive help with daily activities.
· Stage 7: Very severe cognitive decline. They lose the ability to respond to their environment, to carry on a conversation, and eventually to control movement. (Source: www.alz.org)
NEW TECHNOLOGY: An important aspect of treatment is early detection. The FDA approved a new technology to detect Alzheimer’s, called Amyvid. Its radioactive dye is used with positron emission tomography (PET) to visualize amyloid plaque buildup in the brain. It’s designed to be used on adult patients with cognitive impairment. A negative Amyvid scan shows scarce plaques and is inconsistent with a neuropathological diagnosis of Alzheimer’s. It also reduces the likelihood that a patient’s cognitive impairment is caused by Alzheimer’s. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with the disease, but may also be present in patients with other types of neurologic conditions along with older people with normal cognition. In other words, if a patient with dementia does not have amyloid buildup, then the cause of dementia is likely not to be Alzheimer’s. If the scan shows they do have amyloid buildup, their chances of having Alzheimer’s increased. A positive scan does not establish a diagnosis of Alzheimer’s, just increases their likelihood. More research is needed to understand the appropriate use of florbetapir-PET imaging in Alzheimer’s diagnosis. The FDA approval of Amyvid will expand the clinical and research opportunities for amyloid imaging. The Alzheimer's Association has convened a task force with the Society of Nuclear Medicine to develop recommendations for the use of amyloid imaging for physicians, imaging and other medical specialists, Alzheimer families and the general public. (Source: www.alz.org)
Dr. Paul Schulz, Neurologist at Mischer Neuroscience Institute at Memorial Hermann-Texas Medical Center, talks about a new way to diagnose Alzheimer’s.
What is the only way that Alzheimer’s can be definitively diagnosed?
Dr. Schulz: The only way to definitively diagnose it in the past was with a biopsy or if someone passed away and you got a chance to examine their brain at autopsy. We were giving it our best guess as to what they have based on their symptoms and testing them, but we were never really certain about what they had.
What were you looking for in a patient’s brain after they passed that would prove they had Alzheimer’s?
Dr. Schulz: There’s a protein that’s deposited in their brain called amyloid and we only see significant amounts of it in people who have the disease. The amyloid that is deposited is the key. We would do stains on sections of their brain and we would look at the amount of amyloid that had been deposited in their brain. That would tell us that they had Alzheimer’s disease versus any of the other dementias that can look very similar clinically.
Is it high levels of amyloid that signifies that?
Dr. Schulz: Yes, we have criteria. It turns out many people have a little bit of it. It’s a byproduct of various reactions, but if you have a significant amount of it then that’s pretty specific for Alzheimer’s disease.
If that’s the only way to make a definitive diagnosis, how would you make a clinical diagnosis?
Dr. Schulz: Typically people would come in to clinic and say, gosh I’m concerned about my memory, I’m getting lost, or I’m having word finding issues. If they are having memory problems, though, a lot of times a person is not aware of it themselves, so often times family members bring them in. I examine them and I give them things to remember. I ask them to draw things, describe how they get home from where we are, and try to understand whether they have significant issues that might be a sign of Alzheimer’s disease. Then we would typically do some blood work to rule out things that can cause memory problems, like thyroid disease. We would do an MRI scan to rule out strokes, tumors, and abscesses. If we ruled out those things then we would be left with saying, well it’s probably Alzheimer’s disease or one of the other neurodegenerative diseases that looks like it.
So it was kind of a guessing game to some degree?
Dr. Schulz: Yes. I think that we all have had patients that we were certain had Alzheimer’s or pretty certain didn’t have it. But when they would come to autopsy, we would be surprised to find out about five percent of the time we were not in the right area at all. Also you could imagine from a research point of view that we enter people in clinical trials, and if it turns out that someone doesn’t have Alzheimer’s, then it wouldn’t be surprising that a medication wouldn’t work. So in retrospect I’m thinking that some of the patients whom we enrolled, that we thought had Alzheimer’s, might not have and it might have confused our clinical trials in the past.
So now there’s a new tool that was just approved in June?
Dr. Schulz: Yes, it came out the first of June. It’s made by Eli Lilly Company. Before that we had an experimental tool that was available, but the problem was that its half-life was so short, like twenty minutes, that you literally had to make it in the same room as the patient, put it in them and scan them right away. This new agent actually has a half-life of several hours. So it can be made in one spot in town, brought to our hospital, given to someone and then we can wait a half hour to scan them and see whether or not they are depositing amyloid in their brain.
What is the name of the product and what does it do?
Dr. Schulz: The Eli Lilly name for it is Amyvid (and the generic name is florbetapir). It’s a really unique compound; it was actually very difficult to develop. They had to develop something that would dissolve and go through your blood, and cross the blood brain barrier into the brain. There’s a barrier there that keeps things from going in so it had to go across. Then it had to attach to amyloid in the brain. And then, while it was attached there, it had to give off a signal that we could record in the scanner; it gives off a photon. So it had to have all those properties. Not surprisingly, it’s taken several decades to develop a product that actually would accomplish all that, and do it in a reliable way that we could use in the clinic on people with other diseases and different co-morbid illnesses, like cardiac and pulmonary disease, while effectively diagnosing this.
Can you describe what Amyvid does? It produces different colors on the brain images?
Dr. Schulz: What we’re doing here is using colors to be able to see where the compound is attaching. It’s easier for our eyes to see that than black and white. It turns out that in the deeper areas here the product sticks because it’s fat soluble and it sticks to the fats in that area. But, on the outside of the brain there’s no fat and it’s also where all your brain cells are: that’s where you do all your thinking. If we see the compound in the areas along the edges where we do our thinking, then we know that’s specific for amyloid being deposited in the brain. So all of the yellow along the left edge there, on this person’s right side because we’re looking from the feet up, is amyloid being deposited in the brain there. This guy interestingly is still working and he’s very early in the disease. One of the interesting things we have found is that the amount of amyloid doesn’t necessarily correlate with the degree of symptoms the person has. He certainly has the disease, it’s just mild. He can still go to work and talk. He still remembers who I am and he still remembers a fair number of things. He just takes extra notes to be able to remember things from day to day.
It’s FDA approved now, so this has shown that amyloid buildup is the main cause of the disease?
Dr. Schulz: That’s right, this supports the idea that amyloid is important in the disease as we see it in everyone with Alzheimer’s disease.Let me mention that if you take people off the street and do this test, it would be a problem. Some of them will be positive even though they don’t have Alzheimer’s disease. In other words they don’t have cognitive impairment. We think the reason for that is that people lay down amyloid for twenty to thirty years before they develop the disease. So there are people walking around who will have a positive scan who don’t have Alzheimer’s. On the other hand, if you have a patient coming in to your office who has cognitive impairment, and you do the scan and it is positive, we’ve never had a case where it turned out they didn’t actually have Alzheimer’s if we follow them through to an autopsy. So if you have cognitive impairment it’s very sensitive and very specific.
So you could have that high amyloid buildup and not have Alzheimer’s, but everyone who has Alzheimer’s does have that amyloid buildup?
Dr. Schulz: That’s right.
How excited about this are you and for your patients?
Dr. Schulz: I can’t overstress how important it has been for us and how revolutionary it’s been for us who see patients to be able to, for the first time ever really, see the amyloid in their brain and make a diagnosis for them. Of course it makes a big difference in people’s lives when we tell them that they do or do not have Alzheimer’s disease. So it makes a huge difference to be able to diagnose someone specifically and know that our chances of making an error are so much less now. For example, this particular gentleman said, “well I’m not all that bad; I don’t want to take medications that are going to cause side effects.” I said, well if you really have Alzheimer’s disease these medications are going to make a difference and we really want you on them, but if you don’t have Alzheimer’s disease we could take you off.” So he agreed to get the scan and then I was able to tell him, “You know, you definitely have it, but the good news is I can tell you that today and we can get you on those medicines now. Even though you’re having some side effects, we can work with you to get you on them anyway.” So it made a huge difference in his life.
Also, the patient whose wife you’re going to be interviewing had depression on and off during his life many times and honestly he looked very much as though he was just having depression again. I couldn’t tell whether he had only depression or more than that. I diagnose Alzheimer’s by asking people questions, such as remember these five words, and then I ask them again later what the words were. You can imagine that someone with depression, who is distracted by feeling so badly, has a very hard time remembering five words and so five minutes later when I ask them the words they don’t know them. That’s exactly like Alzheimer’s, so how can you tell the difference between the two of them? His MRI scan was okay, his blood work was okay. I didn’t know for sure whether he had Alzheimer’s or not, but his wife is an intelligent woman and lives with him and she said, “This seems like more than his normal depression.” Nonetheless, I couldn’t tell for sure. So I said, well you know what I’ve got this new tool. In fact, he was the first patient on whom I did it after approval, which was on June1st. And honestly, I thought in my heart that he was probably going to be negative and that it was just another episode of depression for him. I was very hopeful that I would be able to give both of them good news. I have to tell you my heart sunk while he was in the scanner and the images were showing up and I could see that it was showing a lot of amyloid right there from the beginning. I knew that I was going to have to go in the waiting room, then, and tell the two of them that, unfortunately, it is Alzheimer’s disease as well as depression and we’re dealing here with something that’s going to have a big impact on both of your lives. On the other hand, the good news is that I was able to tell him the diagnosis then, and not two years later when the depression had gone away. In the past, I’ve always had to follow people until the depression went away, and then test them again cognitively. If they could remember at that time, then they previously just had depression. But if they couldn’t remember things, then it would be Alzheimer’s.
Would a positive impact of the scan be that, if you can start treating AD earlier, then you can keep the symptoms from getting worse?
Dr. Schulz: That’s exactly the idea. We don’t have a cure for AD, but people do better on the medications and so it is important to start them as soon as possible. There are a lot of other personal reasons to know the diagnosis earlier, too. For example, he and his wife have questions about whether he should be driving. Depressed people can usually drive, but if you have Alzheimer’s disease it affects your concentration and your ability to find your way around. If you have Alzheimer’s disease, we tell people not to drive because it’s just not safe.
Also, they’re a couple who are at the prime of their careers, they’re earning money. What if he decides he wants to buy a Porsche tomorrow? If it was you or I, we have a right to make that decision: if we have the money, we can spend it as we desire. However, at this point, if he has Alzheimer’s disease, then his wife can say maybe he’s not making decisions based on what he really wants: his brain is a little different and he may get the idea to have a new car and he might just go out and buy a Porsche, even if he doesn’t deeply desire it. So, I’m able to counsel families in a way that I couldn’t before; for example, by being able to tell this family that he definitely has this process going on in his brain and that’s going to change how he thinks and behaves. It can have a very positive impact that way because families can make better, more informed decisions about what their loved one wants to do: they can think about whether he really wants and needs and deserves that Porsche, or whether it is an impulsive decision that will change in a few hours. Another important change is being able to say to the two of them that they should do things together now while he’s still able to do things, recognizing that next year might be different. In the past I wouldn’t have been able to tell them whether it was going to be different next year. Now I can say that we’re going to do everything we can, but unfortunately he may be different next year and this may be the time for the two of you to spend more time together and do things you want with your family.
How about the impact with drug therapy, is there anything there you can do differently besides starting earlier?
Dr. Schulz: Yes. For example,many people have side effects from the medication and so a lot of people go off of them if they don’t think they really have Alzheimer’s disease. So in this case we can put him on them, but also help them work through the side effects and explain even though there are some side effects I’d rather have a little upset stomach and preserve my brain power as much as I possibly can. In addition to the Alzheimer’s medications, we can focus on managing all the other risk factors for dementia that may alter its course, like treating hypertension, hyperlipidemia, and diabetes more aggressively, emphasizing the need to stop smoking, encouraging healthier eating, and encouraging weight loss. We also recommend physical and mental exercises, which can help the course of AD.
How do you describe this? Is this a breakthrough in your mind? Is it an advance or how would you describe it?
Dr. Schulz: I’ve been studying Alzheimer’s disease for over thirty years. For the first time ever, to be able to actually see this stuff is incredible. It’s incredible diagnostically, but it’s also incredible research-wise. The things that I’ve seen on these scans are not what I would have predicted. Because I previously only saw people’s brain tissue once they passed away and could examine it, I had no idea during life whether amyloid was something that’s deposited everywhere or only in certain locations. We weren’t sure why some people have some symptoms and other people have others. Just as an example:, I have several people with the same Amyvid scan findings but very different symptoms. That tells me as an investigator that it’s not just the amyloid that is important: something else is also important. There must be something about how different parts of the brain in different people are reacting to the amyloid that’s causing symptoms in them. That’s a revolution by itself. Because that’s telling us as investigators to study the amyloid, but there’s something else going on, like inflammation. So we need to look at other things to explain why individuals actually get symptoms from this.
In the other direction I have a guy who has just mild memory impairment. On the other hand, I have a guy who is profoundly affected by Alzheimer’s with exactly the same amount of amyloid. Clearly their brains are reacting differently to it and if I could figure out why one guy is not reacting to it, which might be another avenue for treatment different from trying to get rid of the amyloid. The other research point I would make is that since we can see this for the first time, we can now try things to lower the amyloid level and see whether we are successful. In the past the only thing I could do if I saw someone who was depositing amyloid in their brain was to give them experimental treatments and then I would just have to follow them for many years to see whether we were successful at preventing Alzheimer’s. Now, for the first time, I can take people with early symptoms, or even no symptoms, and see whether they have amyloid. If they do, we can give them different experimental treatments to try to reduce amyloid. Then we can do a scan again after one year, even if they haven’t changed clinically, and see whether they’ve got less amyloid present. It’s revolutionary in terms of being able to study this disease, in addition to being able to tell people something about what’s going on with them, which we couldn’t do up until just six months ago.
Is it an easy test for the patient to do? Are there any conditions that interfere with it?
It’s a very easy test and there’s no pain at all. It’s about a tablespoon full of clear liquid. It looks like water and we just put it in a vein. The person sits in the waiting room for thirty minutes, we bring them in, they lay in a scanner for ten minutes and you’re done. With MRI scans, people get a little claustrophobic in there and have problems with it. This is done in what looks like a CAT scanner that’s nice and open. The other issue is that the previous PET scans we had relied on metabolic activity. If someone wouldn’t sit still, you couldn’t sedate them because it would change their metabolic activity. If they had depression, there were problems interpreting the scan because depression alone would affect the scans. And the medications we were using could affect the PET scans that were looking at metabolism. This new scan isn’t affected by any of those issues so the person can come in there and can go to sleep. If they’re not able to sit still, their loved one can be standing there with them, or we can sedate them. It doesn’t matter if they’re on any medications or not they don’t interfere with this. We haven’t found anything so far that interferes with this and so it’s a very robust test in that regard. It’s very easy to perform and very easy on the patient with no pain at all.
So there are a lot of possibilities then?
Dr. Schulz: It’s incredible. I don’t even know the right English word for it. Breakthrough doesn’t even fully express it: it’s something more. Even revolutionary doesn’t capture it and is a little trite. For someone who has worked on this disease for many years, it’s chilling: for the first time, we can see what is happening in someone’s brain. Up till now, it has been like studying a black box where we just had to infer what was going on inside. Now, for the first time, we can see and study what is happening. This should have a great impact on our ability to care for patients with Alzheimer disease by helping develop cures for this terrible disease.
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Department of Neurology Administrator Coordinator
Memorial-Hermann Texas Medical Center