Behavioral Symptoms in Dementia: Association with Initial Cognitive Phenotype

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:

A first of its kind study from Cleveland Clinic showed that the presenting clinical phenotype of Alzheimer's disease or Lewy Body Dementia, along with neuropathology and a patient's age and sex, predicted the likelihood of subsequently developing specific behavioral and psychological symptoms. This study provides an important window into how the heterogeneity of clinical changes in dementia at initial visit, can help inform patients and their caregivers of the probable course of behavioral symptoms later in the disease course and help guide management. In today's episode, we're discussing these findings and what they mean for the future of dementia practice and research. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute and joining me for today's conversation is Dr. Jagan Pillai. Dr. Pillai is a Behavioral Neurologist in Cleveland Clinic's Lou Ruvo Center for Brain Health. Jagan, welcome to Neuro Pathways.

Jagan Pillai, MD, PhD:

Thank you, Glen.

Glen Stevens, DO, PhD:

So before we dive into the research, I want to start with your intent. As a clinician and researcher, tell me why this research was so important for you to pursue.

Jagan Pillai, MD, PhD:

Glen, I'm sure you face the same situations I have, you have patients and family members walking into your office and one of the main questions is, "Tell me, Doctor, what do I have and what do I expect to have over a period of time?" I diagnose people with cognitive problems, including neurodegenerative diseases like Alzheimer's disease and Lewy body dementia, and one of the questions I get asked is, "So what do I look forward to next?" once you have a diagnosis. We discuss about the nature of the disease, the kinds of changes that they can expect. But so far, there was a disconnect between what I actually told them and what they are going to experience later on, because a subset of these patients have behavioral changes as the disease progresses and I'm sure you have come across the same situation.

Jagan Pillai, MD, PhD:

Managing behavioral changes is the toughest job I have. It's exhausting for the patients, it's exhausting for the family members and it's very challenging for the physician to figure out how best to help these people, because behavioral changes really talk about something very fundamental about who you are as a person and what it means in your social life and how you make meaning of that.

Jagan Pillai, MD, PhD:

When people have these symptoms, so far, we have no way of even understanding which of these people are at high risk for developing behavioral symptoms? Which of them have low risk and what can we tell them and what can we prepare them and how can, as a physician, guide them through this process? That was the main motivation behind this book.

Glen Stevens, DO, PhD:

I'm fascinated by this project, just the scope of it, the number of patients. For our audience, why don't you tell us how you got the patient data? How many patients were in the trial and what types of things you looked at? I'm also curious how long it took you to do the study.

Jagan Pillai, MD, PhD:

Sure. The Cleveland Clinic is part of a network of Alzheimer's disease research centers across the country called Alzheimer's ADRCs or Alzheimer's Disease Research Centers. One of the key goals of the Alzheimer's Disease Research Center is to have a longitudinal cohort of participants over a period of time they get characterized and eventually after they pass on, their brains are evaluated at autopsy to correlate the clinical picture with the underlying pathology.

Jagan Pillai, MD, PhD:

The ADRCs have been in existence since the late 80s and they have a large cohort of patients that they have been characterized. Cleveland has had contributions to ADRC, many iterations, so that was a cohort that was evaluated in the study. Seeing these were patients followed on average about four to five years before their evaluation at autopsy.

Glen Stevens, DO, PhD:

Did all the patients have autopsy?

Jagan Pillai, MD, PhD:

No, a subset of the patients do have autopsy, and then the study focuses on over 2000 patients who actually have had autopsy confirmation. It's very important to know what the autopsy diagnosis of the condition is because until recently, maybe five to ten years ago, biomarkers for making a diagnosis of Alzheimer's disease was not readily available in the clinic. So we still don't have these large numbers of clinically characterized patients with whom we can say with confidence they have an underlying degenerative disease like Alzheimer's.

Glen Stevens, DO, PhD:

I'll just throw out a quick commercial to everybody out there that if you're a member of a consortium or a group as you're a member of, it's a great opportunity to get a large volume of data from a diverse subset of institutions. Not just obviously in the Alzheimer's, but in the tumor field that I'm in or whatever the field is that people are in. If you have access to these, I encourage people to look at clinical trial opportunities in their area of interest.

Glen Stevens, DO, PhD:

Take me through a little bit more of the research. I come to see you, what are my risk factors for figuring out my phenotype and what's going to happen to me down the road? Is it my gender? Is it my age? Is it my specific type of dementia? What's my risk?

Jagan Pillai, MD, PhD:

Glen, you would definitely appreciate this, as a neurologist, the number one thing is localization. We always think about, how do you localize the symptom, and that's pretty much what's primarily done in this paper. It basically makes the connection that if you localize a problem to a certain part of the brain, then you might have problems both cognitive and behavioral issues later in that part of the brain.

Jagan Pillai, MD, PhD:

Alzheimer's disease, just take an exemplary case. It's generally thought about as someone having memory problems initially and over a period of time they develop other kinds of symptomatology. So when you have memory problems, initially, that means that your hippocampus or the medial temporal lobe is involved initially and then the disease affects other areas.

Jagan Pillai, MD, PhD:

What we have found out over a period of time is that this memory onset is only a subset of cases. It is definitely a majority of cases, but we still have significant amount of Alzheimer's disease cases where the initial symptom may be primarily, say language related, where they have aspects of aphasic syndrome, or they have problems with judgment where they're not able to take care of themselves or plan what their daily life looks like. Or they may have primarily visual spatial symptoms where they are difficulty navigating or reading and aspects of that.

Jagan Pillai, MD, PhD:

The key idea that drove this research is that if you have amnestic or memory compliance is coming from the medial temporal lobe. If you're in primary executive or judgment problems, it's likely to involve the frontal lobe. If it's a language problem, it's going to involve the left temporal lobe, if it is a spatial problem on parietal lobe. If you're having relatively focal pathology that starts out, it's also possible that the behavioral symptoms also is going to match the same circuits that are being affected in each of those areas. It's very intuitive, but actually it was never looked into, so this was a kind of formally testing the hypothesis that happened in the rest of the paper.

Glen Stevens, DO, PhD:

I guess one of the things I saw was that, and again, it's probably intuitive that the younger you are when you have your problems, the greater your problems down the road.

Jagan Pillai, MD, PhD:

Yeah. Actually there is a flip side of the coin because the severity of the problem not only relates to the fact that you're being followed longer, it kind of makes sense because the more you follow a person, the more likely they're going to have and develop a problem. What I mean by younger age in this paper is that people having a younger onset of the disease, also have a much more severe phenotype. So that in the Alzheimer's disease field or degenerative disease field, we kind of separate out the young onset cases and older onset.

Jagan Pillai, MD, PhD:

A young onset is not usually considered under age of 65. It's kind of line in the sand that is defined by Medicare criteria, but actually typically they tend to have much more aggressive disease, much more atypical forms of the disease and what we show here is that they also have a higher likelihood of severe behavioral changes.

Jagan Pillai, MD, PhD:

It is kind of different from the typical picture you think about it because you think about older patients having behavioral problems as they're in the nursing homes or things like that, but if you look at Alzheimer's disease or Lewy body disease, that's another condition that we study here, the younger people actually have much more severe problems in the behavioral domain.

Glen Stevens, DO, PhD:

Well, I'm 65 next year, so if I can just get to that point, I guess I'll be doing better, right?

Jagan Pillai, MD, PhD:

You definitely have to celebrate that point.

Glen Stevens, DO, PhD:

What about male versus female?

Jagan Pillai, MD, PhD:

That's an interesting thing. To be honest, we evaluated the differences between male and female, aspects of education, are the genetic high risk factors like, risk factors, because these are common ways in which how their Alzheimer's disease or Lewy body disease, they're also, for example, Alzheimer's disease is well known, it affects women a little bit more than men, whereas for Lewy body disease, it's so skewed towards men, so men have a higher risk for developing Parkinson's and Lewy body disease. In this case, what we found out that in general, men tend to have much more severe behavioral changes than women, but women have a higher risk for some kinds of behavioral issues, things like depression. It's also an interesting difference, which makes me wonder, differences in how the neuronal circuits are different in men and women that's causing these differences in the face of similar pathology.

Glen Stevens, DO, PhD:

I don't think you looked at this at all, but does handedness matter, people that are left versus right handed?

Jagan Pillai, MD, PhD:

We did not look into that specifically, but that's a great question and now that you asked me, I'm curious to see what actually it did show. Because one of the reasons that we saw that language, people with language issues, language deficits, in these kinds of diseases have in fact, the lowest incidence of any behavioral issue.

Jagan Pillai, MD, PhD:

We think that's primarily because the part of the brain that's important for a reality testing and a sense of self, is more on the right frontal cortex, and it tends to be preserved, relatively preserved, when you have such asymmetric involvement like primary language affecting the left hemisphere. I would be curious to see how the right-handed versus left-handed differences play out here as well.

Glen Stevens, DO, PhD:

Jagan, anything with educational levels affecting outcomes with patients with cognitive problems?

Jagan Pillai, MD, PhD:

Yes, we actually try to see if does education play a role in the nature of behavioral symptoms that a patient would experience? Because higher level education actually has been shown to slow down disease progression because of the phenomenon called cognitive reserve, where they compensate for the pathology in some way. And interestingly, we see a similar effect in behavioral changes as well. So the cognitive reserve that you build up through education and I'm supposing through other activities like engaging in social activities or cognitive exercises. There's a potential that they can be actually mitigating strategies for behavioral changes as well, so that's an exciting insight from the study.

Glen Stevens, DO, PhD:

Some of it seems like the good news, bad news. I mean it solidifies, I think things that you probably thought for some period of time, but you have somebody that comes in that's 55 and they're having significant cognitive related problems. I guess you have a more concrete ability to tell them what their course is going to be. On the other hand, it's also pretty tough to have to tell them that, right?

Jagan Pillai, MD, PhD:

Well, I think it is tough. One of the things that I, as a physician really take... I found this very, what can I say, meaningful, is the fact that as part of physicians, it's not only prescribing a medication, it's also making something very challenging that's happening to a person meaningful for them and helping them set goals that make life something that they can build on still in spite of this challenging situation.

Jagan Pillai, MD, PhD:

I find this work kind of filling that role, for example, younger onset patients of a higher likelihood of having language problems. With them, can I reassure them that they're, as far as their, in terms of their behavioral changes and how they relate to people, that's not going to be affected as much. Whereas in people with significant executive deficits or judgment problems initially, I think I would be in a better position to also let family members know what to expect so they can find help much earlier than waiting for things to happen before they find themselves overwhelmed.

Glen Stevens, DO, PhD:

I like that attitude, I'm a kind of rip the bandaid off guy as well. I think it's better to have these conversations early, but you have to find a way to do it and still give hope, which is obviously the difficulty with patients.

Glen Stevens, DO, PhD:

Have you changed what you're doing since the data came out, or this is how you approach patients anyways, it doesn't change since you published the data?

Jagan Pillai, MD, PhD:

No, I actually, one of the biggest surprising things about this data is that it clearly separates out each domain of initial symptoms and the specific behavioral changes. I honestly was not expecting to see such very clear distinct profiles, so I was not actually talking to people about different risks based on their clinical phenotype, but now that we have this kind result it's part of my conversations.

Glen Stevens, DO, PhD:

Sounds like it's important then that we need to make sure we get this information out. What do you see going forward? What's the next step for your research or what are you looking at?

Jagan Pillai, MD, PhD:

What we have followed up, we have initiated study. One of the questions is yes, we know that different phenotypes or cognitive phenotypes are also related to specific behavioral changes. But if we are now trying to tackle a different issue related issue in the sense that when Glen, that there are not a lot of medications that are very effective for these conditions. I mean, we kind of use medications that psychiatrists use and kind of repurpose them in many of those behavioral management situations here.

Jagan Pillai, MD, PhD:

One of the key challenges there is that it's very hard to know which is the appropriate medication in each situation because different kinds of cognitive circuits are involved. We don't know what is the kind of cognitive behavioral circuit that's affected in say specifically, for a hallucination versus a delusion and if that can help us figure out if the medication is likely to be effective and kind of target patients much more effectively for a medication.

Jagan Pillai, MD, PhD:

We have now studies ongoing trying to understand or define the specific circuits that are involved in hallucinations versus delusions in different kinds of different diseases like Lewy body dementia or Alzheimer's disease, so that we can have better targeted therapies for these things or have biomarkers to track these things. That's the next step we are falling up on this on.

Glen Stevens, DO, PhD:

Jagan, this is very exciting research. We are really looking forward to continued input regarding medications and the work that you and your group are doing. Thanks for sharing that with us today, we appreciate it.

Jagan Pillai, MD, PhD:

Yeah, absolutely.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.