Understanding the Signs and Symptoms of Alzheimer Disease-Related Agitation
In this video, Kasia Rothenberg, MD, PhD, geriatric psychiatrist at the Cleveland Clinic Lou Ruvo Center for Brain Health, provides a robust overview of Alzheimer disease-related agitation, including detailing the difficulty in testing for Alzheimer disease-related agitation, the challenges caregivers and family members face when reporting symptoms to clinicians, the gaps in our knowledge that remain, and whether either the current FDA-approved treatment for Alzheimer disease-related agitation or other treatment options in the near future can curb the most prevalent symptoms of Alzheimer disease, particularly agitation.
Additional Resource: https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease
TRANSCRIPTION:
Kasia Rothenberg, MD, PhD: Hi, hello, thank you for invitation. Let me briefly introduce myself, Cassia Gustav Raffanberg, and I am a psychiatrist, specifically geriatric psychiatrist slash neuropsychiatrist. So I'm a kind of a person who indeed covers all the psychiatric presentation of neurologic disorders. I work at the Center for Brain Health in Cleveland Clinic, Cleveland, main campus. And this is my role. We mostly try to help people with all kinds of neurodegenerative diseases. And our bread and butter is, of course, Alzheimer's disease.
Consultant360: How would you describe neurodegenerative disease?
Dr Rothenberg: A brief explanation of what neurodegenerative disease means. This is a kind of a condition where symptoms come with, emerge from the situation that brain is shrinking, neurons are not working properly and eventually die.
So it's a kind of a group of a conditions where our brain basically stops working properly. It's different that, for example, what we see after strokes or any other specific damage to the brain. Most of the neurodegenerative diseases, well, with a hallmark of those diseases, Alzheimer's disease, kind of a develop in the process of aging. So, yeah, those conditions usually occur in people who are older or people who are aging.
But all those conditions, the prevalence of them increase with aging. So the older we are, the more prone to those conditions we are. And all of them are quite prevalent. So it's some, some more than others. Alzheimer's disease, it's quite a common neurodegenerative condition.
C360: What exactly is Alzheimer disease-related agitation?
Dr Rothenberg: So as I told you before Alzheimer's disease, it's quite a prevalent neurodegenerative condition, neurodegenerative disease of a brain. We think about Alzheimer's disease as something which causes our memory loss. And indeed, it is the first sign or symptoms that we notice in ourselves, or we notice in our loved ones, or we notice in our patients. Although so there is this kind of shortcut in our thinking that Alzheimer's disease, it's a disease of a memory loss. It is, but there's like a lot of other symptoms that we should be noticing as early as possible in Alzheimer's disease because it's like naive even to believe that Alzheimer's disease, is only memory loss.
And the symptoms that I talk about, the symptoms that we observe in our patients, they come from the fact that neurons, our neuronal cells, the essence of our brain, stop working properly, and they start showing some signs and symptoms. When you look at in a microscopic way at them that we can recognize now, they start producing, for example, dysfunctional proteins.
Some of those proteins, which we may even detect in a spinal fluid, in the brain, in many other bodily fluids, but this is a kind of a sign and symptom of a process which exponentially increases leading to neuronal demise and death. And of course, this situation leads to all kinds of problems in the way our brain works. It can definitely present first as a difficulty memorizing or thinking really fast, but later on more and more and more symptoms emerge.
Some of them kind of a purely psychiatric, something that we know from completely different aspects of neurology and psychiatry. Some symptoms of depression, apathy, psychosis, agitation, anxiety, et cetera, et cetera, et cetera. Here comes the problem that in Alzheimer's disease, as I described to you, those symptoms that occur in a situation of brain changing or changed brain.
And our understanding of those symptoms we take from what we know from psychiatry, like classic psychiatric disorders, anxiety, depression, psychotic disorders. And we kind of extrapolate this knowledge, which, of course, it's what we do. It's our first technique that we use kind of are there subdisciplines or other diseases. And we don't really know very well what we expect in the situation of changed brain.
C360: What are the gaps in our knowledge as it relates to Alzheimer disease-related agitation?
This is the main gap that we don't really understand very well. We name something “agitation” and the situation that we name when we see somebody with Alzheimer's disease may differ from our knowledge of agitation, per se. Now let me take a step back and tell you a little bit more about those other non-cognitive symptoms of Alzheimer's disease because everybody knows that Alzheimer's disease, it's about memory, or to be a little bit broader, cognitive functions. And we have all kinds of tools to even look at those symptoms.
First of all, we know what to look for. And we have tests. We can give somebody a brief or longer tests which specifically assesses memory. Now, as disease progresses, we see more and more different symptoms, including agitation. Agitation being like a purposeless activity, which does not really seem to be leading patients anywhere and exhausts them. It's a lot of energy loss and a lot of purpose loss. But the most important part is that the those and the agitation may lead to some safety issues. It may lead to behavior that is dangerous potentially. Now, we don’t really have good tools to assess those things specifically in Alzheimer’s disease. And here starts the problem because without knowing how to measure, how to assess, how to even look for those symptoms, we won’t be able to proceed very well.
Now, we know about those non-cognitive symptoms of Alzheimer's disease. We had been like looking at them or trying to research them for long, long time. I would say that the first well-organized studies would take us to 1980s. In the 1980s, I believe it was ’86, was the first tool to assess Alzheimer’s and agitation, we call it the Cohen-Mansfield Inventory. But it’s a tool which requires a lot of time. So it can’t be like immediately used in a clinical practice. So we were trying. We were trying to assess to figure out how to measure agitation with Alzheimer's disease.
And what we learn from that, that the more severe stages of a disease, we observe more and more those non-cognitive symptoms, including agitation. Now, what we learned as well, which may be interesting and important in a clinical practice, is the fact that those symptoms, they cluster. So, for example, if we see agitation, there is a huge chance that it may escalate to aggression or that we should be looking for other signs as well, like for example, psychosis.
So we know that, but still we don't have a good way to measure it. And now I'm talking from a perspective of somebody who have per definition a little bit more time, this is my job, this is what I do, I try to assess and help those people with, for example, agitation or psychosis in the course of Alzheimer's disease, But I would want as well to equip with other providers, like, for example, primary providers. For them, it may be even more problematic. The agitation in Alzheimer's disease as a clinical situation because they don't have a lot of time and experience with agitation period. So maybe creating some easier way for them to notice it, to harness it would be the way to go. And this is a huge gap in our knowledge.
C360: Can you describe the difficulty in testing for Alzheimer disease-related agitation?
Dr Rothenberg: You know what, it may come and go, and they are like kind of different types of agitation. Of course, the most obvious one is a motor agitation when somebody like, for example, is pacing, spacing, correct? So something that we can see. But they are a little bit more subtle forms of agitation, like for example, being fidgety or playing with something, or making repetitive noises, or eating or drinking something over and over and over again. A repetitive sequencing of questions. So there's a lot of other forms of agitation, other than motor agitation, which are hard to really notice. And obviously, as every other human behavior, those symptoms may come and go.
So yes, many, many times we rely on reporting from a family member. Because when we interact in an office with a patient, we do not notice those signs and symptoms. So it's another difficulty that we may not be able to notice those signs and symptoms during the visit. It would be ideal because this would give us like a full understanding of what caregivers, family members are noticing, but it may not happen. So we have to rely on somebody's reporting.
C360: Can you describe the challenges caregivers or family members face, particularly when reporting symptoms to clinicians?
Dr Rothenberg: It may be a gap in language. Many, many times I ask people specifically to describe, to give me an example, to describe those concerning situations to me. Many times, obviously, in their reporting, people may use or may categorize something incorrectly. The most common thing is using the term “anxiety” for agitation, for example. Or describing as anxiety certain signs and symptoms of psychosis, so it’s extremely hard. And of course, there is a certain type of urgency here because some of those motor agitations may escalate, and family members know it and they are afraid that something may happen.
C360: What are the treatment options for Alzheimer disease-related agitation?
Dr Rothenberg: And of course, we don't have any specific treatment for agitation. So all we do, we target symptoms. The first thing first, we know for a fact that treating, in general, cognitive symptoms of Alzheimer's disease may give us some time, may not only hold the process of progression of the cognitive symptoms, but may protect patients from going into those situations like agitation or psychosis. So there is a little bit of a knowledge that we have.
And here comes my, I think it's a good thing to know that treating Alzheimer's disease, cognitive symptoms of Alzheimer's disease can eventually change the course of a disease not only for cognition, but for neurobehavioral symptoms, those symptoms of agitation, psychosis, et cetera, et cetera. So this is one thing.
The other thing is using the techniques and tools that we have, which are non-pharmacologic. So we shouldn't be going to pharmacology, to medication first, there are some tricks and techniques which can redirect the patient. So it's always a rule to try non-pharmacological methods first. And this is extremely hard, especially at home. It's a little bit easier for professional caregivers or professional providers who are trained to notice certain symptoms of agitation. And there is a trick as well and some experience which is needed to notice those behavior which may escalate and de-escalate them. So there is a lot of knowledge and in the way how to use non-pharmacological techniques, how to help de-escalate symptoms of agitation.
However, certain types of agitation we know may escalate, even if we use all kinds of a redirection and redirection techniques. This is the moment we reach for medication. And now, for long, long time. We did not have anything which was studied for this particular indication. Now very slowly, this gap is being filled. We have one medication, which was approved by FDA specifically to target agitation in Alzheimer's disease. The medication name is brexpiprazole. And if you look at all the pharmacological groups of medication, this medication falls under the umbrella of antipsychotics. We know as well that certain type of antidepressants, we call them SSRIs, which stands serotonin re-uptake inhibitors may help with agitation as well.
For ages, physicians, nurse practitioners were using psychotropics, psychiatric medication from different groups as well, unfortunately off-label. So, at this point, we have only one medication which had been approved specifically to target agitation and a lot of different medication compounds in the pipeline.
C360: Looking ahead, do you anticipate more treatment options combatting Alzheimer disease-related agitation in the near future?
Dr Rothenberg: Good question and I see a little bit of a development, I'm glad that finally something started happening here in this particular field.
It's still, there's like huge disproportion. A lot of researchers on different levels are interested in those preclinical stages of Alzheimer's disease. Well, we are all involved in thinking how to recognize signs and symptoms as early as possible. There is a huge investment in the treatment specifically to target cognition in as early stages as possible. Not much. For long, long, long time, we did not have a lot of interest.
Maybe it was an interest, but not enough development in those later stages of Alzheimer's disease. To give you the best example, we don’t really have antidepressant which have been specifically to treat depression in the cause of Alzheimer’s disease. So we use medication based on our knowledge medication or from other fields of medicine.
Having said that, I always like to see something happening because if one medication had been approved immediately, people would think maybe how to change an approach a little bit. Maybe other medication with a similar pharmacological profile would be even more beneficial in targeting, in treating this symptom.
And of course, when we talk about studies or studying something, immediately we must take a step back and think about how to assess the situation. So, it back to our first, my first statement, we have to create some tools, specific tools, to assess agitation in Alzheimer's disease. So yes, I believe that of course one medication won't make a lot of difference, but it will focus, first of all, on the later stages of Alzheimer's disease, on those neuropsychiatric symptoms, and bring a little bit more attention to this field, which I hope we will result with better tools, more studies, and a little bit broader armamentarium for us clinicians to help patients with agitation or psychosis or depression or apathy. It's not easy because once again those studies imagine that everybody is different. We must recruit, observe or assess how medication works for quite large group of people to be able to calculate or to notice significant difference. So yeah, it's a huge challenge.
There are some developments which are interesting to me since I am from my education and neuropharmacologists. So very recently, like a week ago, we all as a field, we went to a large conference, specifically focused on Alzheimer's disease. And yeah, I noticed some good, promising results of a clinical trials specifically for agitation or psychosis.
Interestingly, the medication, in general, medications which are being tested or studied to address agitation in Alzheimer's disease are kind of mixed-profile medications. So those are compound which binds to multiple different receptors in the brain, modify at least three different types of circuitries in in the brain. So yeah, I believe we will expect, we may have soon a little bit more than only one medication to target agitation.
C360: What is the take home message from this discussion on Alzheimer disease-related agitation?
Dr Rothenberg: Maybe not specifically for our audience, but obviously there is a lot of interesting science behind what is going on in the brain when a person presents with agitation. And we fortunately, there are like groups of scientists who are like studying this aspect of Alzheimer's disease. Like what is going on in our frontal cortices, how our amygdala, which regulates our emotion, work when brain atrophies, when we have signs and symptoms of Alzheimer's disease.
What type of neurotransmitters change and how they change in Alzheimer's brain? What is happening to all those circuitries that regulates our mood, our affect, our motor activity, our interest, our motivation. So this is like really fascinating field, and I hope more and more people would bring their tools and knowledge and skills to this aspect, you know, behavioral aspect of Alzheimer's is. Thank you.