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Mony de Leon, Ph.D., explains a new way to detect the earliest signs of Alzheimer’s disease in healthy people so they can get the most out of therapy.
Ivanhoe Broadcast News Transcript with
Mony de Leon, Ph.D., Neuroscientist,
New York University School of Medicine, New York, New York,
TOPIC: Early Alzheimer’s Detection

Why did you decide to do this study?

De Leon: The current pathology of Alzheimer’s disease, which of course, is only done after a person dies shows a very significant development of the hippocampus and the enterorhinal cortex. This led us to surmise some years ago that this was a very likely early target because of its massive devastation by the middle and end of the disease.
What did you set out to prove by doing this study?

De Leon: We set out to learn whether we could detect during life, the involvement of those two brain structures in individuals who were either asymptomatic or having mild symptoms. Then after the passage of time, to see if damage to those areas would actually predict which persons would deteriorate.

How long is Alzheimer’s developing before is presents symptoms?

De Leon: That’s a very good question. The estimates for how long Alzheimer’s develops prior to symptoms is really a topic of great speculation and interest. There were some studies done some years ago in Germany about Autobahn accident victims that showed that there was actually a detectable Alzheimer’s disease-type change in the brains of people in their 20s and 30s, who were otherwise healthy people. We don’t know how long it takes for Alzheimer’s disease to progress in the brain to the point of producing symptoms. We don’t know when it starts, we don’t know if there’s a trigger that actually precipitates the event. Right now, it looks very much like a disease like arthritis, which people develop over their life span. In some patients, it doesn’t become symptomatic and doesn’t really affect their quality of life, and they go through their entire lives either denying they have arthritis or arguing that only once in a while do they get a little ache and pain.

If Alzheimer’s is caught early, what can be done to help the patients?

De Leon: There are a number of exceptionally exciting experimental paradigms that are available today. Perhaps the most exciting of all are these new vaccines that are being propagated around the world. The vaccination approach has been demonstrated in numerous animal model studies to rid the brain of some of the lesions of Alzheimer’s disease, and it actually made some of the animals perform a little bit better. And in the case of younger animals, it prevented much of the Alzheimer’s disease from actually forming in the first place. Human studies that have used the vaccine are only in their infancy. There’s only been one study that has been run, and it had really mixed results. Right now that type of study is being redone, and there are some new studies that are now being proposed in the next year. I know of two new studies that are being developed for use of the vaccine in humans to see if Alzheimer’s disease can be removed from the brain and the weight of Alzheimer’s progression in the brain reduced.

What does the MRI actually show?

De Leon: What the MRI shows is a layout of the brain, a structural layout of the brain, and an MRI can be used in an variety of ways. The way that we chose to use it 10 years ago, which continues to date, is to actually look at brain structure using the MRI in a way that allows us to measure the size of structures and the physical appearance of structures. This is giving us views of the hippocampus and enterorhinal cortex, and we have made numerous measurements of the size of these structures using MRI and have learned that these structures are shrunken in size prior to the patient’s becoming symptomatic. So the MRI offers a view of the relative vulnerability of certain brain regions over others, but it’s more than MRI because a very similar kind of information can come out of PET scan. A PET scan, which is positron emission tomography, measures the brain’s glucose consumption, and we find using PET scan a virtual identical map of vulnerability to patients that are pre-symptomatic. They show changes in the enterorhinal cortex and hippocampus prior to developing symptoms as well.

When say there’s shrinking, what does that shrinking show? That the patient is losing competent functions?

De Leon: Well, the shrinking is a physical parameter. Like leaving a grapefruit out on the table for a month, it will get smaller in size because the water evaporates. Well, that’s what shrinkage is. It’s a change in the water content of the brain, it’s a change in the mass of the brain, and the brain gets smaller. Shrinkage, in the case of Alzheimer’s disease, is restricted to a very small number of regions, hippocampus and enterorhinal cortex.

Tell us what the shrinkage actually shows.

De Leon: The shrinkage is basically a structure getting smaller, and in the case of Alzheimer’s disease, the target anatomy that we have been after that proved to be correct was the hippocampus and the enterorhinal cortex. These are structures that are preferentially getting smaller in advance of patients getting sick. In other words, when these structures are smaller, they have some predictive value as to who’s going to develop memory loss and ultimately Alzheimer’s disease.

Is that because those two areas of the brain focus on memory?

De Leon: Those two areas of the brain are major players in the brain’s memory system. The memory system is complex and widespread, but those two areas are clearly among the most important areas that the brain has for capturing the information and deciding what to do with it, where you want to put it, and when you want to remember it. So, those areas are really instrumental in memory and have been known for 100 years to be instrumental in memory. The relation of those areas to memory function is not new. What is new is the selective damage to the hippocampus as part of Alzheimer’s disease and the enterorhinal cortex as part of Alzheimer’s disease.

How difficult is it to isolate those parts of the brain?

De Leon: It is difficult. They’re small, they move around because when the brain shrinks, they change a little bit with appearance, so you need machines that will actually be able to zoom in on with precision those regions of the brain. In the case of MRI, you have a pretty good target. In the case of positron emission tomography, it’s been a real challenge to do this. The resolution, or the resolving power of the PET scanner, is not as good as the resolving power of the MRI. You see different things, and what we’ve learned is with the right technology, both MRI and PET, we can make measurements with both technologies on the same anatomy.

Who would be a good candidate for this study?

De Leon: Uh, are you busy later? The question of candidates for the study, it’s a study. One has to understand, it’s really a study that’s fundamental to human aging. In other words, how do we age? How does our brain age? Our brain doesn’t age uniformally, different parts of the brain age more rapidly than others. Some of that is very consistent, of course. Some of that identifies individuals, and the patterns are really largely not understood.

I think that if people have a family history, I think that people who are interested and want to participate in research, I think people who want to contribute their time and learn about their own aging, those individuals who want to contribute to the knowledge fund, in general, in terms of understanding the general aging process are all extremely valuable and should participate in research. I think one of the things that we’re facing now for the first time, the dilemma, is why healthy people should come to hospitals to participate in research. Because the focus of these studies has moved from sick people to healthy people, and this is sort of contradictory in terms of what people are thinking of when they consider coming to a hospital setting. They come generally in need of help, in need of medication, or in need of advice, but now we’re asking people to come who may not need that, because they are themselves, as they’re getting older, the potential target of these investigations. We need those people to prove these ideas and demonstrate early detection and ultimately capture Alzheimer’s disease and cure it.

How significant is this study in early detection of Alzheimer’s?

De Leon: It’s the first demonstration using MRI that shows you can detect in normal individuals a change in the brain, even during the period of normalcy, that predicts future memory impairment. So the brain is changing even when the patient remains normal, and then years later, demonstrates the clinical change. So, this is a landmark observation.

I know there’s no cure for Alzheimer’s, but if you detect it early enough can you stop the progression?

De Leon: Well, this is very important ground, but also very shifting sand. The prevention of Alzheimer’s disease has never been demonstrated. So, you’re working with constructs and models and ideas about how control of risk factors might influence the course of Alzheimer’s disease. Among all the risk factors that exist, they all share in common their attack on the vascular system of the brain. So by controlling those risk factors, there are some studies that are ongoing, that are attempting to see if they can modify the course of Alzheimer’s disease, and ultimately, that will lead to prevention studies. For example, high blood pressure and diabetes can be controlled, as they are risk factors for Alzheimer’s disease. Is it possible to control the onset and progression of Alzheimer’s disease? We don’t know the answers to that. We are in the process of getting those answers now. It is possible that that thinking could save a few people or delay the onset or prevent the onset for certain people. It is unlikely it would work for everyone. There will be other preventive strategies that will be required. Alzheimer’s is a complex disorder, having many possible genetic driving points even though the sporadic disease has no known major gene that’s causing the pathology.

It is common to hear early detection is the best cure for other diseases such as cancer. Would you say the same thing applies to Alzheimer’s?

De Leon: Well, it’s the only way to get prevention. Unless you put it in the drinking water and give it to everybody, there’s no way to get around the problem of early diagnosis.

You were quoted as saying, “Now we want to combine this technique with measurements of certain Alzheimer’s related proteins found in the cerebral spinal fluid.” Could you tell me about that?

De Leon: Well, the brain images, the MRI scan, the PET scan, they are not specific, meaning that because a part of the brain shrinks, it doesn’t mean that it has to be Alzheimer’s disease that’s causing that shrinkage. There are many factors, other diseases, other conditions, that can cause shrinkage to that same anatomy, making it difficult to interpret the shrinkage. You need other evidence. Well, other evidence can be derived from blood and from spinal fluid. The spinal fluid surrounds the brain and is part of a waste disposal system of the brain. As a result, it captures proteins and other products of metabolism of the brain and allows them to be studied. So by using modern procedures to virtually painlessly and without very limited risk of headache or infection, remove spinal fluid from the lower back. It allows one to do an assay for proteins that are known to be specific to Alzheimer’s disease. So the combination of the MRI with the study of the proteins that are in the brain allows us, we think, to improve the specificity and thereby make the observation that Alzheimer’s can be diagnosed in its early phases, perhaps even pre-symptomatically, with a high degree of confidence that it is Alzheimer’s disease.

If a patient with advanced Alzheimer’s came to you, would this still benefit him?

De Leon: It would benefit the science probably more than it would benefit them. The probability that the clinician is wrong about somebody having advanced Alzheimer’s disease is very low. So the benefit then to the individual, in terms of their immediate care, is low. But there are certain extenuating circumstances. There are diseases that mask as Alzheimer’s disease, which when treated as Alzheimer’s disease, can cause the patients further problems, so the circumstance is rare, but it has some limited value. It is much more valuable for science.

This article was reported by Ivanhoe.com, who offers Medical Alerts by e-mail every day of the week. To subscribe, go to: http://www.ivanhoe.com/newsalert/.

END OF INTERVIEW

This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.

If you would like more information, please contact:

Henry Rusinek, Ph.D.,
New York University School of Medicine
(212) 263-6537
hr18@nyu.edu
http://www.med.nyu.edu/people/hr18.html