University Place  Brad Christian Alzheimer's Disease in Adults with Down Syndrome  April 27, 2013 UP868   cc >> In listening to us go over these details of Down syndrome. Today I want to talk to you about some ongoing research that we're participating in here. The name of the project is entitled The Natural History of Alzheimer's Disease in Adults with Down Syndrome. So, to go over a brief outline of what I want to talk about today. First of all, I'll try to make the connection of why we're interested in studying Alzheimer's disease in Down Syndrome, give you a little bit of a background on Alzheimer's disease, and then discuss amyloid imaging. Now, I'm going to talk in these first couple slides about amyloid. It is one of the pathological signatures that follows Alzheimer's disease. I'm going to explain it in more detail in a couple slides, so be patient with me as I mention that word in the next several slides. And then the last two points, I'm going to kind of jump back and forth. The storyline is somewhat mingled there between recent findings of the role of this amyloid in Alzheimer's disease as well as discussing the details and preliminary findings of our ongoing study so far. 

So, first of all, the motivation. Adults with Down Syndrome are at a very high risk for developing Alzheimer's disease, with most individuals over the age of 40 starting to show these amyloid deposits. So, to clarify that point, people over 40 are not showing Alzheimer's disease; however, they're starting to display some of the pathology that accompanies Alzheimer's disease. So the goal of this project is to actually track these pathologies in adults with Down Syndrome and then follow them throughout several years to gain an understanding of how these changes occur in Down Syndrome as well as track the person's functioning over time, both their cognitive and living skills over time. So overall, this research offers us a real opportunity to gain a better understanding of exactly what's going on in Down Syndrome, I should say, with its higher incidence of Alzheimer's disease, hoping that we'll provide insight, maybe target development of therapies for the future not only for Down Syndrome but also for the general population in Alzheimer's disease research. So the prevalence of dementia in the general population is relatively low at younger ages. Up to about age 65, still only 5% of society is afflicted. However, it increases significantly the older you get. By the time you're in the mid-80s, we're looking at almost a third of the population showing dementia. So, of course the number one risk factor for Alzheimer's disease is age. 

The older you get, the higher your risk of developing it. Now, if we look at the Down Syndrome population, here we have, in our 40s, roughly 10% of adults will show dementia. We go into our early 50s and that almost doubles up to close to 20%, and then if we integrate off the entire fifth decade of life, roughly a third of individuals will have dementia at that stage. So comparing that to the general population, we're about 30 years earlier showing the same level of incidence. So there's definitely something going on within the brain that is causing this accelerated aging going on in Down Syndrome. I'll give you a brief overview of some of the characteristics. I'm sure everybody's familiar with this in Alzheimer's disease. It is a type of dementia which is a progressive deterioration of cognitive functions that hinders a person ability to live independently and take care of their daily duties. Alzheimer's disease is the most prominent type of dementia. Roughly 70% of the cases of dementia are Alzheimer's disease, and the characteristics accompanying Alzheimer's disease include a real compromise of cognitive skills such as their judgment and planning type of behaviors as well as memory and also alterations in emotional behavior. 

So of course Alzheimer's disease is a public policy issue. Over five million Americans have Alzheimer's disease, over a hundred thousand here in Wisconsin. The seventh leading cause of death. And I'm sure as everybody is well aware of, our baby boomer population is aging, and they're starting to approach the age where they're going to be at a much higher risk for developing Alzheimer's disease. So I show our two little symbols on the bottom of the slide there. One is the Wisconsin Alzheimer's Disease Research Center, which we have here on campus. We work closely with the ADRC. Professor Sterling Johnson is a collaborator in this project, and we use some of the resources of their lab as well as our own IDDRC here at the Waisman Center. So these are both very highly competitive processes to get these centers funded by the National Institute of Health. We're very fortunate we have both of these resources here on campus, and they really enable us to participate in research such as this project. 

To move onto, I just talked about some of the symptoms accompanying Alzheimer's disease, there actually is pathology that accompanies it and very well characterized. So when Dr. Alzheimer first looked at autopsy type of samples of brain in the early 1900s, he noticed two signature characteristics in looking at the tissue. They're referred to as tangles and plaques. So on this slide I will just give you a brief introduction to what the plaques are. So if we consider this little cartoon here of a healthy neuron, it has these projections that go out, dendritic projections. They can then form junctions with other nerves, form synapses and communicate effectively, making our brain do the remarkable things that it does. Well, the structure of these projections here include something that are called Tau proteins. You could kind of envision them as being the steel reinforcement rods in concrete pillars. What happens is a process referred to as phosphorylation can alter the structure of these proteins, and they become more or less unraveled and form these little nests of disoriented strands here. And these are, of course, toxic to cellular function, and we end up with cell death due to the presence of these Tau proteins or Tau pathology. 

So the brain slice is here. These kind of show the progression of what's seen in Tau pathology. And these have been characterized by autopsies. So right away we see it kind of forming in the prefrontal cortex as well as the entorhinal cortex down here. As we the symptoms of Alzheimer's disease start to manifest themselves, we see it spread out further into the cortex, and by the time we have severe Alzheimer's disease, it has spread throughout much of the brain. So this is all I'm going to say about tangles. I hope in the years ahead I will be talking more about actually imaging this Tau pathology. Right now there's some very exciting research going onward. Biomarkers are being developed to actually image these in the brain. We are not quite there yet, but I think in the very near future, the next several years, we'll see more research in this area. 

So what I want to talk more about are the plaques, and they're referred to as beta amyloid plaques. And I'll give a little bit of an illustration of these in these cartoon pictures. So, this purple structure here, this protein, is tethered to the surface of the cell. So if you think back on that previous slide, I had that healthy cell, these structures are tethered to their surface. The exact function of them, APP is amyloid precursor protein, their exact function is still not clearly defined. However, they're present in all brains. And what happens under normal functioning is you have this enzyme called alpha secretase, and it comes and will cleave off this tethered portion here, releasing the amyloid precursor protein into the cellular space, and then the gamma secretase comes and clips off the bottom part of it. So you're left with these two fragments, the soluble, that's what our SAPP is here, as well as this little fragment here. And under normal processes, the brain can clear both of these fragments out and we don't get any accumulation of these. However, there's a different pathway that the brain can undergo in removing these APPs, and that is shown here. 

So rather than the alpha secretase, we have something called the beta secretase, and that cleaves the protein off in a slightly different location. And now, when the gamma secretase comes and clips off the rest of it, we're left with a longer fragment here. So if we keep our eye and compare these two structures here, we have a different fragment left in that case, and that's referred to as our beta amyloid peptide. So here you can see this is our beta secretase here, now in a larger illustration. It comes. These peptides are somewhat sticky and they can adhere to one another, and when you get several of them, they form oligomers onto fibrils as they continue to combine, and, ultimately, they can congregate into these large amyloid beta plaques. And these plaques are what coat the cell surface and lie on the nerve cells, and eventually the nerve cells can tolerate them for a while, but they will succumb to them and it is believed that they are toxic to the cell and will cause cell death. So this is referred to as the amyloid cascade hypotheses of Alzheimer's disease implicating these plaques that have been always present in Alzheimer's disease when looking after a person has died from the disease. So what's the tie in with Down Syndrome? Well, of course, Down Syndrome is, here's the chromosome profile and illustration. Down Syndrome is Trisomy 21, three chromosome 21s, and I want to now draw your eyes to the other one. 

It's just an illustration of the chromosomes in a person, and it numbers all of them. And this particular slide I took from the literature shows the genes that are implicated in Alzheimer's disease, that is genes that seem to be prevalent with a higher incidence. Too here are shown the presential in one and two. These have been implicated in familial Alzheimer's disease or early onset. But if I draw your eye to chromosome 21, there's an indication there, and on that is a gene that is involved with the production of this amyloid precursor protein. That is a protein that's tethered to the cell surface. So the running theory is that because there are three chromosomes, there's an overexpression of this gene and an overproduction of amyloid precursor protein. Therefore, people with Down Syndrome are making more of it. Now that theory isn't absolute watertight. A lot of research is going into that area. 

For example, chromosome 21 also has genes associated with this beta secretase. So research is going on in that area too, but I think as far as the most straightforward explanation, an overproduction of amyloid precursor protein is most widely embraced at this time. So, we are going to use medical imaging to study this problem of Alzheimer's disease in Down Syndrome. And, first, I will give a brief explanation. In the past, I've spent a lot more time talking about these imaging modalities that we use. I'll just over them roughly. So we're using magnetic resonance imaging. We position the person in this magnetic field. In there, radio frequencies wave then can be used to alter the signal and enable us to get contrast, and we get, in the brain, these very exquisite images of the structural folds within the brain. We can distinguish gray matter and white matter and really help us characterize the morphology or structural changes that may be happening in the brain. 

And we also use positron emission tomography, and this operates off a different mechanism. With PET imaging, here is a scan. The scans look kind of similar, but in this case, we actually take what are called tracers, small amounts of a particular drug. And the drug can be whatever you are interested in studying whatever process, and you put a radioactive label on it, I have indicated here, you inject that into a person, and this small amount of drug is then incorporated in with the normal physiology in the body. Biochemically, it behaves just as the drug would if it weren't labeled, and the radio label provides a little beacon to tell where it is being taken up or binding or incorporated into the body. So, here is a corresponding PET image of the brain. It's the same slices that we have here. And the particular drug we use for this illustration is one that targets the serotonin receptors in the brain. We have some research ongoing in the serotonin system, and by labeling a drug that targets those receptors, we can see the function of that particular neurochemical system. Now, PET imaging has been used quite extensively in research of Alzheimer's disease, and most often the first radiotracer used was FDG, or fluorodeoxyglucose. 

It's sugar. So if any of you know of anyone who has had a PET scan primarily in the area of oncology imaging, tumor imaging maybe for tumor staging, this is the radiotracer that's been used. Tumors, of course, have higher metabolic demands. They take up more of this and provide the contrast in imaging and allow the physician to examine the extent of disease. Now the brain also uses most of its energy or derives most of its energy from glucose too. So, under normal conditions, we inject the radiotracer into the person, you're going to see the brain incorporated, and that's what's shown here. And I'm sure while I've been talking about this you've all been kind of comparing the two images and seeing what the difference is between them. And I'll give away the answer and put little arrows in there to direct your eyes. So that area in Alzheimer's disease is where we're seeing decreased metabolic function. Right here in the parietal cortex as well as this area referred to as precuneus. 

So these are really signature binding patterns that we see in this. And this has been very helpful, the use of FDG imaging, in kind of first characterizing biochemical changes that are seen in the brains of living subjects with Alzheimer's disease and has really helped to target research and focus some direction in studying this disease. However, the issue here with FDG is we're studying it after somebody already has Alzheimer's disease. One of our goals is to, the scientific community in general, is to find tracers or markers that can locate chemical changes earlier in the brain, maybe before any of the symptoms of Alzheimer's disease are present, and allow that to give us earlier insight into some of the changes going on. And this is one of the radiotracers or biomarkers that have been developed for that purpose. So here is the chemical structure, and here is our radio label on it. So this drug targets those amyloid plaques that I showed in the earlier image. It will enter into the brain and this drug will bind to them. And that gives us, allows us to actually see the accumulation of these plaques in a person. So the compound that I'll be referring to is carbon 11 label, that's our radioactivity, and then PIB, or PiB is what I'll refer to it as. 

That stands Pittsburgh Imaging Compound B. So the investigators at the University of Pittsburgh, who are collaborators with us on this grant not only for their development of the compound but also for recruiting and studying Down Syndrome subjects, are involved. So here's an example of a image with this PiB. You inject it into a person, give it a little time to incorporate, about a half an hour, and then position them in the PET scanner, and this is what our image looks like. So this is actually a subject with Alzheimer's disease, and you can see we use these color bars to kind of enhance the images. It actually doesn't make the brain glow in yellow or orange or red. These are assigned by our computers when we visualize it. And you see the intensity right here on the outside of the brain, the cortex. That's where the plaque can accumulate in a couple different areas. Here's that precuneus area I was showing you on the other side, as well as the frontal cortex. 

And then the bottom row there shows what this tracer looks like in a healthy control. And you can see if we focus on the outside, there really isn't any elevated uptake. Now, you see some bright spots in here. Right there and there. That is in the white matter. It's kind of a non-specific area. We really aren't concerned about anything in there. So, the take-home message, we now have a PET tracer that allows us to image these amyloid plaques in living people. So, some of the early research just kind of focused on characterizing it in different states or stages of Alzheimer's disease progression. Here's a very early study done in the literature where they compared healthy controls, for the most part, showed very low levels of this binding. 

Alzheimer's disease is AD. Everybody showed elevated binding. And then an early stage of Alzheimer's, mild cognitive impairment, is kind of a mixed bag here. Some have elevated binding, some don't. So, this particular tracer and others like it are now being used to fully confirm a diagnosis of Alzheimer's disease. That is, if somebody's showing the cognitive symptoms of Alzheimer's disease, such as memory problems or behavior changes, we could do a scan, and if indeed there is no presence of this amyloid, we could state that no, it is not Alzheimer's type of dementia. It could be a different type of dementia, but it's not Alzheimer's because these plaques are not evident with it. And in the early days, this was used to make a conceptual model of Alzheimer's disease. That is, what's going on chemically in the brain and then what are we seeing as far as symptoms. And here's some of the biomarkers. 

I'll just draw your eye to the light green one right here. That is the presence of amyloid that we would get imaging with this PiB tracer. So, initially, it was conceived that it comes at a very early stage, just presymptomatic, and has some period of rapid production, and then it kind of levels off. It is not until it's been there for quite some time that we see, now look at the dark green curve, the cognitive changes in the brain starting to become more evident. So, the take-home message from this, as I said, this is more or less a cartoon. It's intended to look like somebody sat down and drew it with a marker without a lot of adhering to data as you're drawing it. The point is the presence of amyloid in the brain comes very early. So, as I said, active research has been going on for the last decade now looking at the time course of this amyloid plaque in the brain. The focus of our study now is to examine what is the progression of this amyloid in people with Down Syndrome because they have the higher incidence and earlier incidence of Alzheimer's disease. So, this is a flier to our research protocol describing it. 

And what we're doing, there's two centers, ourselves and the University of Pittsburgh, we're  looking to recruit 84 people with Down Syndrome that are not showing signs of dementia. And the youngest we're allowing in is 30 years. So 30 years and older, we're studying scanning on people who are not showing dementia. So here are some of the experimental details. It's a two-day study. They come in the first day and we do a series of neuropsychological type of tests. So, to show you here, the tests involve both the caregiver, they are asked questions, the DSDS interview is the Down Syndrome dementia scale, they help by going through this questionnaire, determine if indeed the individual has dementia. And then the Down Syndrome individual will be taking these neuropsychological tests. And here's an example shown. I'll talk about these more in detail. 

And then the second day, they come in and we do the scanning of them. We do both an MRI scan and a PET scan to look at these amyloid plaques in the brain. So here I'll show you some of our preliminary results. I show we have 47 subjects I'm reporting here. We have acquired more since we last presented this data, and now we're up to around 60. So our recruitment is going well. And here are some of the details of our recruited population. We're having an average of right around 40 years old. So, as I said, we're including anyone over 30. Relatively balanced between males and females. 

Heavily Caucasian population we're looking at so far. We're working very hard to include minorities into this project and continue our efforts on that. And I will kind of show you some of the early results. So here are two of the imaging studies indicating subjects that have elevated binding of this PiB or elevated presence. So, just to give you an explanation of how to look at these, we focus on, right here is the cerebellum of the brain, and in general you do not see the accumulation of amyloid plaque in that area. So that's kind of our reference region. So we see how much we have in the cortical areas of the brain and divide it by that, and that ratio determines whether someone is going to be called PiB positive, which means they have an elevated level of amyloid plaque in the brain, or PiB negative, meaning we aren't seeing elevated binding in their brains. So, of the 47 that I showed on the previous slide, roughly 40% of them are showing elevated amyloid or the presence of amyloid plaque in their brain. So here is that data. Yes. 

>> Just to clarify, those subjects of those 19 show no dementia at this time. >> Exactly. Everybody in this protocol, right, is not showing any signs of dementia. I'll give some more details on that in a little bit. Here are the results. So now I'm just showing you kind of each individual. The threshold that we used that determines this PiB positivity is drawn here in the yellow line. So anyone above it, we call positive; anyone below it, we call negative. So what I want to point out in this slide is the youngest subjects, right around 30 to 35, we are not seeing anybody with elevated amyloid plaque in their brain. However, once we get above that age, we are starting to see accumulation. 

Obviously we are continuing to gather more data. But the trend of the data you see is consistent with the general population in the sense that the older you get, the more likely you are to have amyloid plaques in you brain. Now of course the general population, our axis would be much different. It might start at 70 and go up to 85 in that case. So, we are seeing individuals with higher binding. And, as you pointed out, no one is showing any signs of dementia. So now we take that first day of testing and we start to see if any of those results are influenced by their PiB score or their PiB status. Do they have elevated binding or not? And one of the metrics we measured was independent living skills which uses a test called the Vineland Adaptive Behavior Scales. It measures a person's ability to communicate, to live by themselves, can they hold a job, cook for themselves, their socialization skills. And between the two groups, we did not see any significant difference. 

Now you see, they're not spot on straight across; however, we subject this to statistical tests, and it is not significantly different between them. So, the presence of this PiB status, PiB plus means elevated amyloid binding, does not seem to alter or affect, at this point anyway, their independent living skills. We've looked at one of tests to examine behavioral problems using a re-screen for maladaptive behavior. Behavioral problems would include aggression, paranoia, depression, anxiety, autistic type of qualities. And in this instance, we aren't seeing any difference in behaviors due to the difference in the presence of amyloid binding. However, once we go away from or we head towards the measures that really interrogate the cognitive processing, we're starting to see more interesting results. So here is a test called the cat and dog strip test, and it measures executive control and working memory. So these images are presented to the people, and they look and they will identify them as cat, dog, dog, cat. And then the test gets more difficult where now you have to switch the trial naming of them. So you would see the cat and you'd say well that's a cat, but you suppress the desire to say cat and say the other name. 

So you would say dog, cat, cat, dog. It gets a little bit trickier. Between the two groups we didn't notice any difference in the numbers of errors that were observed. Everybody got the same amount right. However, the amount of processing time took a little bit longer with the group with the elevated amyloid binding. Suggesting it was a little bit more taxing cognitively to arrive at the right answer. Here was another one, a visual/spatial type of test called the Corsi block-tapping. Now, the psychologists who give the exam will tap a pattern out on these blocks that you see there, and then the subject will have to mimic that pattern and then be asked to go in backwards, go in reverse. That is, memorize the pattern, now take it backwards. And here in the forward direction, we do not see any difference. 

However, the one involving a little bit more memory, thinking of reversing the sequence that they saw, we actually are seeing differences there with the PiB plus group having a lower accuracy in conducting that. And then the other, I should say another memory test where we're seeing differences is a verbal working memory using a test that actually, they're told a story and then following that, they're asked to recall particular details about the story. And in that, we see the recall is not as good in the PiB positive group. So these are our early studies. Once again, these are probably not signs that a caretaker might notice. You really have to highlight the function and interrogate a particular system before they're evident, but we are seeing differences here. And I think if you all go back to that slide I showed you with the age and the PiB binding on it, you'll notice the PiB binding was higher as you got older. We did account for age in calculating these statistics so that was incorporated into it. So now if we go back to that earlier conceptual model, I want to go back into the general population and research that is going with Alzheimer's disease. Data is really starting to be more actively analyzed and studied. 

Now we're getting to about 10 years of data flowing in. More longitudinal studies, that is studies where measurements have been made in the same person over time, are starting to be analyzed. And this early model is starting to be modified using current data. So this is a publication that was just in Lancet Neurology in April of this year. And they kind of modified that graph. The red line here is the beta amyloid which is analogous to the light green one I showed you earlier. So, from the data that they're starting to analyze now, it looks like there really is no period of rapid amyloid accumulation. It's just kind of a slow, steady process all the way. And a time has been starting to be attached to the X axis. So this is actually 30 years in the general population. 

The brain could be accumulating this amyloid plaque until this vertical line here indicates where Alzheimer's disease is actually diagnosed. So this also is taken from that, and it's a confusing plot I wanted to display for that very reason because of all the spread in the data. So what this graph shows you, on the Y axis is the change in this PiB score. So they come back over time, and from time one to time two, that is a change that we're seeing. And then on this axis would be their baseline PiB score that they had. So, that is, is there a period where you're seeing a real rapid deposition of the beta amyloid in the brain? And in general, it's relatively flat. This model is drawn in here as kind of a modification of the previous one. But what I really wanted to point out in this is the huge spread in the data and any ability of this PiB to actually be predictive of when a person would develop Alzheimer's disease, how much is bad, what dose the changing rate mean. There's just tremendous variability in the population. So a person could, at this point, not get a test, get some measure of PiB in their brain, and have a physician tell them, okay, you've got 5.4 years until you'll be diagnosed with Alzheimer's disease. 

There's just too much variability, too much we still have to understand regarding this whole trajectory. But it does give a little bit of a rough time course, and here is kind of the summation of this particular paper which I thought was important. We have some period where the beta amyloid starts to accumulate, and once that period has started, about 12 years, on average, until a person would be considered positive for it and then another 19 years until you would see somebody actually manifest the symptoms of Alzheimer's disease. So this is something we would like to closely examine in Down Syndrome. What is the time course that we're looking at there? What is the rate of accumulation as we bring people in a second time and scan them? Is there an accelerated period? How wide will this be? How wide will that be? We hypothesize it's going to be more compressed, but we're still just at the beginning now of studying all of this. And with that, I'll come to my conclusions. Advances in healthcare have dramatically increased the longevity of adults with Down Syndrome and now approaching 60 years. So the Down Syndrome population is going to start having to contend with many of the illnesses that the general population does in aging, and Alzheimer's disease is one of them. So, in our subjects, we saw about 40% of these subjects had PiB positive. And even though they did have elevated amyloid binding, they did not show any signs of dementia, and their living skills were not affected at this point. 

And, as I showed, we were starting to see some alterations in cognitive function. But I should stress too, that was considered a cross-sectional type of study where we looked at everyone as a function of age. In this protocol now, we're going to be bringing people back and we'll be able to compare each person with themselves if they are actually decreasing compared to how they were before. So it will be much powerful findings that we can report with much better accuracy. So, future directions. We've been funded by the National Institute of Health to increase our sample size, we're up to 84 now, and repeat these measures in people longitudinally. We hope that our findings will provide very valuable information and we can continue to get funding for this and really make it a long-term type of project. And with that, we have to acknowledge our funding. We're thankful for that. As well as the investigators, of course. 

Marsha, director here, has been very, very helpful in making this research happen, our colleagues at the University of Pittsburgh, but first and foremost, our participants, and by participants I mean not only the individuals with Down Syndrome that come in but also their caregivers. They're taking, more or less, two days, I heard somebody point that out before, the demands on time and the difficulty in just getting to general appointments, but to actually participate in research, we're very grateful. It truly is a special group that will help us out with this, and we're very thankful for that. With that, I'll stop my talk and entertain any questions. [APPLAUSE]