Mechanisms of Alzheimer's Disease Found Through the Post-Mortem Brain Autopsy Program

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research, discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: Postmortem brain studies of individuals who have had Alzheimer's disease or other dementias, as well as those who did not, provide a unique opportunity to elucidate how these disorders impact the brain. In today's episode of Neural Pathways, were discussing Cleveland Clinic's Postmortem Brain Autopsy Program and how the program's findings contribute to our understanding of Alzheimer's disease mechanisms and influence clinical care. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Jim Leverenz join me for today's conversation. Dr. Leverenz is a neurologist, researcher and Director of the Cleveland Clinic Neurological Institute's, Lou Ruvo Center for Brain Health in Cleveland, Ohio. Jim, welcome to Neuro Pathways.

Jim Leverenz, MD: Thank you. Thanks for invitation to talk.

Glen Stevens, DO, PhD: So, Jim, as I get older, sadly I become more interested in what you have to discuss, but I have to say I'm not ready for your autopsy table yet. So let's get started with an introduction to the Postmortem Brain Autopsy Program. Can you give us an overview of the catalyst for the program and what is involved?

Jim Leverenz, MD: Sure. So one thing that we know when we see people with a question to say Alzheimer's disease, a dementia as they get older, is we're not as accurate as we'd like to think we are in terms of the actual diagnosis. And particularly when we're doing research around this area, we really want to know what the underlying cause is. And there's a lot of the actual new therapies for things like Alzheimer's disease that are being examined that are really based on findings from autopsy. So getting back to that, I think really being more precise in our diagnosis and there are reasons we use some of the brain tissue for some of our particular research programs as well. I would say one thing that's happened over the last several years is we've had a number of NIH funded projects that require an autopsy program to be part of them. And that's something that's really driven us to open this program up.

Glen Stevens, DO, PhD: Now in collaboration with your autopsy program, I understand you also have a bio bank or a bio repository. Can you talk about that a little bit and when did that start?

Jim Leverenz, MD: It started actually before the autopsy program, right when I came to the Cleveland Clinic over eight years ago. One of the areas that I'm really interested in was how can we more precisely diagnose people with memory disorders in the real world, in clinic, not waiting until we have an autopsy for example. It doesn't do much good there. So that was really the purpose of that.

And we draw blood, we do some spinal fluid testing. You can include things like genetics and brain imaging as a part of that. But really trying to, we use the term deep phenotype individuals with memory disorders, really get a feel for what's going on. And then ultimately linking that to our autopsy program so we can come back and say, "We know that this was Alzheimer's or this was Lewy body disease or frontal dementia." And then link that back to all that information that we had gathered over the previous years. And that really helps us move this field forward and with the ultimate goal of being able to precisely diagnose what's happening in the brain while someone is alive, as well as having very specific therapies down the line.

Glen Stevens, DO, PhD: So when you study the postmortem brain samples, what are we looking for? What are you finding?

Jim Leverenz, MD: Well, it ranges from, we just take a brain weight, for example, how big is the brain? Is this big or small for the particular individual? But what we look for under the microscope are changes that many of us have heard about the amyloid, the tangles that we see in Alzheimer's disease. Mentioned Lewy bodies is a kind of change that we used to see only in Parkinson's, I think we only saw in Parkinson's, but now as to a kind of dementia called Lewy body dementia. Changes we see in frontal dementia and of course stroke, vascular disease. One other point I would make is that we're finding as we do these studies in more detail now, is that it's actually relatively uncommon for someone to have only Alzheimer's or only Lewy body disease or only stroke. And that is if people get older, unfortunately we have multiple things going on that can cause problems with thinking skills.

Glen Stevens, DO, PhD: And both your postmortem program and also the bio repository, is this just a Cleveland Clinic program or is this a citywide program?

Jim Leverenz, MD: Well, the Alzheimer's Center program, which is part of this, is a citywide program. That's and collaboration between ourselves, Case Western Reserve University, University Hospitals, and actually the VA is becoming involved as well. So this is a citywide program. The program for Lewy body disease that we have funded is actually an eight site program around the country. We're the coordinating center for that, but we're working with a number of investigators that have specialty expertise in that area. And really bringing all that thinking skill into it, but also allowing for us to recruit participants from a variety of places around the country.

Glen Stevens, DO, PhD: So as I'm paying attention to some of the literature out there, I saw some recent exposure on exercise in Alzheimer's disease. And they spoke that those that have frequent exercise and I guess we can always discuss what that level is, it was somewhere just under 10,000 steps a day, I think, that in patients they reported increased hippocampal volumes and also improved neurogenesis. With the data that you're collecting, can you look into that? Will you have that type of data available to you?

Jim Leverenz, MD: We have some of that data. I would say more specific data. We have actually is a collaboration we have with Dr. Steve Rao who also has an NIH grant to study exercise in cognition in older individuals. And he's particularly looking at people who carry genes that increase people's risk for Alzheimer's disease. And so as part of that study, he's really looking very specifically, how does exercise change things like you mentioned the hippocampus, the brain volume, but also cognitive skills. So it really will give us a very specific idea of what kind of exercise is needed. I don't think any of us know exactly what's enough exercise. I think 10,000 steps a day is a good marker. I'd like to say I always get my 10,000 steps in, but doesn't always happen.

Glen Stevens, DO, PhD: So I'm just curious, with all the testing that's available for the public these days, people will do a profile and their APOE4 will be affected. Are you seeing patients come to you and want to be involved with your bio repository program based on some type of genetic tests that their family gave them at Christmas?

Jim Leverenz, MD: It's a great question. Yes, that sometimes happens. I think we probably get a lot more people who come in because they've had a family member who developed dementia or Alzheimer's, Lewy body disease and they're worried. And they want to also not only help the community as a whole, but also have somebody looking at them in a very specific way so that they can be followed over time and we can determine if something's coming on as they get older.

Glen Stevens, DO, PhD: So in terms of getting back to the autopsy program, do you know the numbers approximately how many a year you're looking at? How many autopsies are being done in the consortium?

Jim Leverenz, MD: For the Lew Body Consortium, I think we had, we probably somewhere in the 50s. So we're getting about 10 to 12 a year. Because we've been going for about five years now. We do think they'll be, as we increase the number of people participating in study, those numbers will likely go up. On the Alzheimer's Center I would expect similar kind of expectation.

Glen Stevens, DO, PhD: And what findings would be especially significant for future research or clinical care with your autopsy study for dementia?

Jim Leverenz, MD: I think that the critical thing from my perspective is linking the autopsy results to what we saw while a person was alive and participating in our pre autopsy studies. So we really like to have people participate, for example, in our Alzheimer's Center. And that ranges from people with Alzheimer's, normal elderly controls, people with Lewy body disease. We're very interested in those individuals. And linking that information we gather as they're participating in the study on an annual basis to what we see ultimately at autopsy. Because that's going to link all that information together so that when I'm in my clinic and I'm seeing somebody with mild symptoms or maybe even when they're not having symptoms yet, their primary care doc, are there tests that we can do to predict their risk and have us intervene at a very early stage?

Glen Stevens, DO, PhD: Yeah, it seems like a great opportunity for learning as well, right? I mean, we think clinically somebody has a disorder and then they go to autopsy and it's different. And I wonder how do we go back and reteach that? Is there a system for that where we can somehow educate the clinicians involved with the care of that patient?

Jim Leverenz, MD: Sure. I think obviously one way is to publish those results in medical journals. The other is to of course give people feedback. The physicians, for example, who are taking care of somebody who did ultimately come to autopsy. So we do release that information to them. Release it to the families as well. So that's the way that we kind of pass that information so people can be more sophisticated. I do think, and it's just my own personal opinion, that at least currently that it is good for people to at least see a specialist once to have a more specific diagnostic workup done and an opinion. Doesn't mean that their primary care clinician can't manage this, but having some input on exactly what's going on as best we can tell, can be useful.

Glen Stevens, DO, PhD: So autopsy then going on for well over 100 years for various disorders, including Alzheimer's. What are the new technologies, techniques, that have become available to enhance the clinical applications?

Jim Leverenz, MD: Well, primarily the things that we've been able to develop over the last 20, 30 years, and this has been a progression over time, is we have antibodies that we can use when we're doing the analysis of the tissue to see if we're seeing changes that we link to specific disease processes. I think most people have heard about amyloid in Alzheimer's disease. We have antibodies who can detect that specific amyloid and we can see how dense the deposition is in the brain. Similarly, in Alzheimer's, we see another chain called tangles that are made up of a protein called tau, spelled T-A-U, and we have antibodies that can pick that up as well. So we can actually very specifically make a pathologic diagnosis of Alzheimer's.

Similarly, we have antibodies for the Lewy bodies that we see in Lewy body dementia, as well as Parkinson's disease. Changes that we can see in certain kinds of frontotemporal dementia. So we have these newer tools now so we can be more precise. As I mentioned at the very beginning though, with these new tools, we're realizing that many people have multiple changes going on simultaneously. So a very common thing is to see both Alzheimer's and Lewy body changes at the same time.

Glen Stevens, DO, PhD: So I know that I'll see patients and they'll have had brain volume studies done with their MRI. Is that correlating with the autopsy studies or are you guys looking at that or has anybody looked at that?

Jim Leverenz, MD: No, that is a part of our research studies actually, is that we do the automated brain volume studies. There is a reasonable correlation between loss of brain volume in certain areas, particularly for example, in Alzheimer's disease. Part of the brain called the hippocampus is important in putting and storing in new memories, does tend to shrink as the disease goes along. And in that context, we can look at that and say, "Gee, this increases our concern that this might be Alzheimer's." Now if anybody's been watching the news in the recent past, there's been a lot of excitement about new potential therapies for Alzheimer's, particularly around the amyloid that we see in the brain. We're going to want to use these tools, try to tell us what's the likelihood this person has Alzheimer's disease, so we can give them appropriate therapy. These therapies are not, as far as we can tell so far, miraculous, but they do seem to be impacting the disease and we're all very excited about these possibilities.

Glen Stevens, DO, PhD: So I understand you have some collaboration as well with the Prion Center at Case and interestingly, in clinic today, one of the physicians asked me, he was looking at a MRI scan of a patient that had an abnormality and somebody had done an LP on the patient and sent the CSF off for prions. And they had mentioned to me that the tau was quite elevated. And they said, "What do you think that that means?" And I said, "Well, I'm going to talk to Dr. Leverenz today, maybe he'll help us with that." But I said, "It's possible, I guess that it could be a non-specific finding of just having an abnormality in the brain that you could see the tau elevated. I guess it's also possible that it could represent that they have an underlying disorder unrelated to the lesion that's in the brain of a degenerative disorder." But thoughts on that?

Jim Leverenz, MD: Sure. So we tend to see, as you mentioned, tau is to some degree a non-specific finding. It generally indicates some sort of brain injury or ongoing, what we would call neurodegenerative process. There are certain kinds of neurodegenerative diseases that tend to cause that tau to go really quite elevated and certainly prion disease is one of those. Thankfully, we actually have a specific test now called RT-QuIC where you can actually measure the aggregated prion protein that causes prion disease or mad cow disease as many people know it. And we used to depend a lot on the total tau sort of as an indicator, but not a direct diagnostic. But now we have that specific RT-QuIC. So somebody, let's say who has an normal or doesn't have an RT-QuIC for prion positive, but has an elevated tau, probably has something going on, but it probably is not due to prion disease.

Glen Stevens, DO, PhD: So can you talk to us a little more about your collaboration with the Prion Center and how that's interacting with your Alzheimer's study?

Jim Leverenz, MD: Sure. You never know, right, as you move along how things can become very important. But what we have found at that same technique that allows us to measure aggregated prion protein, particularly in the spinal fluid, allows us to see some of the aggregated proteins we link to other diseases. So one area that I'm particularly interested in and collaborating with the Prion Center on is measuring synuclein, the protein that's linked to Lewy bodies in dementia, Lewy bodies, and Parkinson's disease. So using the exact same technique to determine if they're aggregates of these synuclein proteins linked to Lew body disease actually look like they're going to work very well. So it is a opportunity to use a similar technique for another diagnostic category. And prion disease is relatively rare, important, but relatively rare. Lewy body disease, we think that there's almost 1.5 million Americans with that in various forms. So very common problem.

Glen Stevens, DO, PhD: So other future directions of your program, where do you see it going?

Jim Leverenz, MD: Well, thankfully, actually, as you probably know, the government, the US government and especially NIH, has made neurodegenerative disease of aging or aging related memory disorders a high priority. They've given us a bypass budget. So we've been very successful with grant funding over the last couple of years, and now we really need to get the work done. Most of my work is what I would call patient based or participant based, so we're really looking forward to looking at people over time. Both with normal aging and with these neurodegenerative processes to figure out what's going on over time, getting better diagnosis and more accurate diagnosis at the same time that we're hopefully getting some of these new therapies coming out that are what we would call disease modifying, not just symptom modifying, but disease modifying.

Glen Stevens, DO, PhD: I was also reading today that with the graying of the baby boomer population and the importance of neurologists, that we've got a big deficit. And they were talking about how many neurologists we're going to be short of in the next 10 or 15 years. So clearly the work that you're doing is very important. What's the answer for that? How are we going to look after all these patients with neurodegenerative disorders?

Jim Leverenz, MD: Well, I think there are people out there who have expertise that we can call on. Geriatricians, for example. In our own group here at the Cleveland Clinic, we have something we call the Center for Brain Health. And we have a number of different types of clinicians. We have neurologists, we have geriatricians, we have a geriatric psychiatrist, a sleep specialist, as well as a group of advanced practice clinicians such as nurse practitioners, physician assistants. And we work as a group together to really help handle the load that we see. And as you might imagine, we see a lot of people that are concerned about their memory or family members concerned about someone in their family with memory loss.

Glen Stevens, DO, PhD: Yeah, I think that's a great multidisciplinary group that you have going on and really sort of shows where we need to move with the field, that it's not just one individual that can look after these patients, but individuals from different disciplines that will bring different skill sets to help manage them. Because there's just, the reality is there's just not enough neurologists to look after them. So I'm thankful to hear that, as I say, as I age.

Jim Leverenz, MD: Well again, yeah, I'm aging as well, so we're all a little bit worried.

Glen Stevens, DO, PhD: Jim, I really appreciate the information you've shared with us today. Any closing thoughts that you'd like to share with us?

Jim Leverenz, MD: I think that part of our comprehensive research and clinical program, no one data point does it all, no one test. But linking the clinical and the pathological changes together are quite powerful.

Glen Stevens, DO, PhD: Well, Jim, thank you for joining us today. This is incredibly interesting work and I applaud your efforts in this area and I look forward to following your research in the years to come. Thank you for joining us today.

Jim Leverenz, MD: Thank you for having me again.

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