Andrew N. Wilner, MD; Ronald C. Petersen, MD, PhDDISCLOSURES
Andrew N. Wilner, MD: Welcome to Medscape. I’m Dr Andrew Wilner. Today I have a special guest: Dr Ron Petersen. Dr Petersen is the lead author of a paper recently published in JAMA Neurology, entitled, “A New Framework for Dementia Nomenclature.” Welcome, Dr Petersen.
Ronald C. Petersen, MD, PhD: Thanks, Dr Wilner, for having me.
Wilner: Dr Petersen, you are a professor of neurology and an expert in the dementia field. Tell us about this paper. I read it and it’s pretty long and detailed. They talk about getting granular, and it got pretty granular about dementia. Why was it important to do that?
Is Your Alzheimer’s the Same as My Alzheimer’s?
Petersen: It all began several years ago at the Advisory Council for the National Plan for Alzheimer’s Disease. A bunch of us were sitting around the table, as we did four times a year in Washington, and it became clear that when one of us was talking about Alzheimer’s disease, the person sitting next to you may or may not be interpreting Alzheimer’s disease in the same framework as you have.
By that, we came to realize that the terms are being used commonly — dementia, Alzheimer’s disease, frontotemporal dementia — but people are not using them consistently. The Advisory Council then charged a subgroup of us to go out and look at this issue, and see whether we could add some clarity to it by trying to dissect how people are using these terms and bring some consistency to it.
With that as a backdrop, we formed a committee of people from various walks of life who come across people with dementia, cognitive impairment, and Alzheimer’s disease. We tried to see what the issues were that people were facing when they started using these terms. That’s the backdrop of how it came about.
As we got into it, we decided that we were probably going to need some subgroups to look at various issues, so we broke the overall committee into three subcommittees, including one on research, one on clinical practice, and one regarding public stakeholders. Those groups met independently, discussed the issues back and forth, and then we would all get together periodically to share our thoughts and to try to see what the issues were and how we might address them.
Wilner: When you say that everyone wasn’t really on the same page when it came to terminology, was that physicians vs laypeople, or was that even within the physician community?
Petersen: Good question. Believe it or not, it’s even within the physician community, it’s even within the research community, and it’s clearly among the public stakeholders. We ran across a situation where the scientists, if you will, at a meeting, would say, “We followed a group of patients who went from mild cognitive impairment to Alzheimer’s disease.”
We realized that doesn’t really make sense because mild cognitive impairment is a collection of symptoms, a syndrome, and Alzheimer’s disease is a specific disease with biologic characteristics. When we realized that was happening very frequently — and is still happening frequently — we tried to look at the big picture from the perspective of how we can simplify this.
We came up with the notion that when we’re talking about any of these diseases — and again, we were charged by the Advisory Council who was dealing with Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, and vascular cognitive impairment dementia — that we thought people should probably address these from a syndromic level and from a pathophysiologic perspective.
Take Alzheimer’s disease, for example. We thought that people, when talking about Alzheimer’s disease, should be clear. Am I talking about the clinical picture of somebody who has a memory impairment? Maybe some other reading or thinking problems, and it’s affecting daily function, so it’s dementia, and it’s been going on for a long time, so it must be Alzheimer’s disease.
Or were people talking about Alzheimer’s disease as a biologic entity? You have to have plaques and tangles in the brain or evidence of amyloid and tau through some biomarker to make it Alzheimer’s disease.
Symptoms vs Pathophysiology
Petersen: Once we appreciated that that was the crux of the problem, we then came up with a framework that really broke the diseases into the syndromic stage of the disease and the pathophysiologic stage of the disease.
Again, with Alzheimer’s disease, we asked questions: What cognitive domains might be involved, including memory, language, attention, and executive function? Then we graded each of those cognitive domains on severity scales, broadly speaking: none, minimal, mild, moderate, and severe.
We realized also that these diseases are not just cognitive. We talked about behavioral features. We talked about motor features and some other features of these disorders, and then asked the clinician to outline the individual syndromic characteristics and grade them on a severity scale. Then we would come up with the clinical syndrome, realizing that is one way to describe the diseases.
Again, on the other side, we have the pathobiology or the pathophysiologic characteristics. Do we have any evidence that the person may have amyloid, tau, alpha-synuclein, TDP-43, or vascular contributions to characterize the diseases? Then we would ask the clinician to put together the syndrome and the pathophysiology, if we know it, and that’s how we would characterize the disease.
We did not tell people how to develop criteria for Alzheimer’s disease, frontotemporal dementia, etc.; rather, we just ask people to be clear, when they’re describing these entities, as to whether they’re talking about them clinically, pathologically, or a combination of clinical and pathologic features.
Wilner: Thanks for explaining it. That was very clear. It sounds much like what we do as neurologists when we see patients. You get the history and you try to define the syndrome. You don’t have any test results yet. Then it kind of guides you: Oh, this patient has hallucinations before they have cognitive impairment; maybe that’s going to be Lewy body disease. Or It’s been going on for a long time; maybe it’s Alzheimer’s disease. It started with memory.
The syndrome, that’s very traditional. Then we get into the testing, including skin tests for alpha-synuclein or tau and amyloid. I agree. It makes more sense to be clear about what you’re talking about.
There’s always been this feeling that, well, you have dementia and it’s too bad. It was interesting for the neurologists to set up the nosology, but from a practical point of view, it didn’t make much difference. But now, we’re starting to see new treatments. Was that part of the driver to get all this sorted out?
Petersen: It seems applicable now, but in fact, we started this exercise before the disease-modifying therapies for Alzheimer’s disease were available. We anticipated that that would be the case, and hopefully for the other neurodegenerative diseases as well. It becomes extremely important to try to characterize the patients clinically and then put it together with any of the underlying pathobiology you may know about because, ultimately, I think many of these cognitive disorders are going to require combination therapy.
This means that if we have biomarkers that characterize whether this individual has some amyloid component, maybe some tau component, but also an alpha-synuclein component, we will now attack these disorders with, perhaps, multiple drugs. It set the stage for that, but in all honesty, it predated the development of the disease-modifying therapies for Alzheimer’s disease.
More Than One Type of Dementia
Wilner: It does muddy the waters a bit that patients can have more than one type of dementia simultaneously, right?
Petersen: Absolutely. In fact, that’s the rule these days, especially as you go up in age. Maybe in the seventies, it’s a little bit isolated in regard to a single disease or a particular disease that is particularly impactful in this individual, but when you get to the late seventies and eighties, it’s almost the rule that there will be multiple copathologies present. Whether somebody is going to respond to a drug may very well be dependent upon whether he or she has these other multiple morbidities.
I think that’s going to be the case down the road, where, wouldn’t it be nice if when we go in to see our personal physician, and the personal physician says, “Hey, we’re going to do a lipid screen to see how your LDL, HDL, and triglyceride levels are, and we’re going to do a cognitive screen from your blood to see if you have amyloid, tau, alpha-synuclein, and TDP-43”? Because hopefully we’ll be able to treat them individually with therapeutics that are targeting those individual pathologic features.
It would be nice if we are able to do that down the road. (Not today or tomorrow.) I’m thinking that, ultimately, that will probably be the road we’re taking.
Wilner: That’s pretty exciting. Now that the paper is published, how do you get the word out that this is the way we should do it?
Petersen: This was what we call the first phase of the exercise. The second phase of the exercise is now going to pilot this framework in actual clinical settings. We’re setting up a program where we will be looking at specialists, clinics, neurologists, and psychiatrists, but we’ll also be looking at primary care settings. We will be looking at the way people do usual practice right now.
Then we will give them some schooling in regard to, “Hey, how about if you use this framework where you describe the syndrome, then you look at some biomarkers, and you help explain that to your patients and their families?” We’re going to do pre- and post-testing in regard to understanding what’s going on in the clinical setting with and without the framework.
We’re hoping that the framework now is going to clarify the complex situation for the clinicians, for the patients and families, and for the clinician communicating with the patient and families.
Wilner: Dr Petersen, you’ve done a terrific job in explaining this approach to nomenclature. Is there anything you’d like to add before we wrap up?
Petersen: Again, we’re not prescribing anything to anybody as to how to define these diseases. We’re just trying to help people reflect on how they do it. I think it is going to enhance the communication among scientists, among clinicians, and hopefully, with patients and families.
Wilner: Dr Petersen, I want to thank you very much for joining us on Medscape.
Petersen: Thanks, Dr Wilner. I appreciate it.
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