Coping with Attention, Learning and Memory Challenges after Transplant

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Coping with Attention Learning and Memory Challenges after Transplant.

May 1, 2023

Presenter: Michael Parsons, PhD, ABPP,  Massachusetts General Hospital/Harvard Medical School

Presentation is 58 minutes long, including 18 minutes of Q & A

Summary: Cognitive issues, such difficulty with attention and memory, are common after a bone marrow transplant. This presentation discusses why they occur, tests to determine the extent of the problem and treatments available to address these problems. (In this presentation, the term bone marrow transplants is meant to include bone marrow, stem cell and cord blood transplants.)

Highlights:

• Research has established that “chemo brain” is a real phenomenon after chemotherapy and transplant.
• Chemotherapy and transplant can impact various types of cognition including executive functioning, motor skills visual spatial skills, language skills and memory.
• Most chemotherapy- and transplant-related cognitive problems are temporary and potentially reversible with medical and/or non-medical interventions.

Key Points:

(04:46): Cognition refers to the skills of thinking.

(05:12): Executive functioning is the highest level of cognitive abilities.

(06:07): Motor skills are part of cognition and refer to things like strength, speed and dexterity of movement.

(06:28): Visual spatial skills include not only your visual acuity and making sure that you have an adequate field of vision, but also your ability to put together the information coming from your eyes to make sense of what you're seeing.

(07:20): Cognition includes language skills, such as word retrieval and the ability to express yourself.

(08:21): There are two different kinds of memory:  working memory and recent memory.

(17:40): We know that certain brain areas may be particularly at risk after chemotherapy, such as the hippocampus, and we also know that the fibers that connect widespread brain areas seem to be more vulnerable to disruption than a lot of other functions.

(22:29): Often, after chemotherapy, patients are able to do most of what they want to do, but it is harder than usual to do it. 

(35:32): Computerized brain training programs can help keep your brain active, but no more so than engaging in any other brain-stimulating activity.

(36:57): Perhaps the most important piece of brain health is physical exercise, which we know is important to promote growth of new nerve cells even in the adult brain.

Transcript of Presentation:

(00:01): Lynne Spina: Welcome to the workshop, Coping with Attention Learning and Memory Challenges after Transplant. My name is Lynne Spina and I will be your moderator for this workshop.

(00:12): It is my pleasure to introduce today's speaker, Dr. Michael Parsons. Dr. Parsons is an assistant professor at Harvard Medical School, and a neuropsychologist at Massachusetts General Hospitals Pappas Neuro-Oncology Center. He has more than 20 years of experience as a neuropsychologist, and specializes in cancer and cognition. Dr. Parsons provides neuropsychological evaluations for adults, addressing the cognitive issues that are caused by cancer and its treatment. These evaluations assist in diagnosis and treatment of medical and psychological conditions that affect brain function. Please join me in welcoming Dr. Parsons.

(01:09): Dr. Michael Parsons: Well, thank you very much for having me. It's a real pleasure to be a part of the BMT InfoNet Survivorship Symposium this year in 2023. I'm glad to be able to reach as many people as possible dealing with these issues.

(01:28): I do want to mention, before I begin, that I have some roles in pharmaceutical company consulting, as I've listed here, and some publications that earn me some royalties. Those roles do not impact the information that I'm sharing with you today.

(01:49): Overview of Talk: Speaking of the information that we're going to be sharing today, our goals are to discuss the cognitive problems that transplant recipients and others who are receiving chemotherapy tend to experience, and how those problems relate to the functioning of different brain networks and systems. I'll spend some time talking about neuropsychological evaluation, what that is, and how it might be helpful for someone who's dealing with those kinds of cognitive problems, and then provide some background, in terms of the science, that tells us about what causes those problems and how they evolve over time. Finally, we'll wrap up by talking about how to cope with those problems, treatments that are available, and things that are coming in the future.

(02:37): We will discuss the different types of cognitive symptoms associated with bone marrow transplant. To spell this out a little bit more clearly, as we talk about cognitive symptoms, we'll discuss the different kinds of thinking skills that are affected, the severity and extent that those typically take, and how those relate to different brain systems. We'll talk about many of the factors that can cause those symptoms, including, of course, the role of chemotherapy, which is often an important part of the induction phase in bone marrow transplant, as well as numerous other problems that can occur as you're dealing with any serious medical issue, including fatigue, sleep problems, stress-related impacts, and side effects related to other treatments or the medical condition itself. And then finally, we'll talk about the evaluation and treatment of those symptoms, including how those cognitive abilities relate to the brain itself.

(03:32): Research has established that chemo brain is a real phenomenon.  To start with, I think we have to address the elephant in the room, this concept of chemo brain, which has, for many years, been a somewhat controversial topic. It was a concept that was originally introduced by patients, people who had been through treatment with chemotherapy, bone marrow transplants, and other types of treatments, who were noticing problems with their thinking, their memory, their attention, their processing speed, and asking their doctors about it.

(04:04): In the early years, these kinds of concerns tended to be downplayed, and it led people to questions whether or not chemo brain is "real." Well, there's been a lot of research into these problems over the past 20 or more years, and I think it's fair to say now that it's no longer a question of whether or not chemotherapy affects the brain. Rather, now we're talking about how chemotherapy affects the brain, what structures or systems in the brain are most at risk, and how those effects manifest in terms of cognitive problems in your daily life.

(04:46): Cognition refers to the skills of thinking. Next, I want to talk about what I mean by cognitive. I've used this word a lot, and really, it just refers to all the skills of thought. That could include basic functions such as your ability to speak, your visual input, other perceptual skills, but also higher-level functions like memory and concentration.

(05:12): Executive functioning is the highest level of cognitive abilities. The term executive functions is often used as kind of an umbrella term, which really covers the highest level of cognitive abilities. We're going to talk over those in more detail in just a minute. But for now, just keep in mind that the executive functions are those high-level abilities, the ones that really distinguish human cognition from other species.

(05:41): There are many different domains of cognition or areas of cognitive skills that we evaluate or worry about when people are going through chemotherapy or experiencing cancer or having a cognitive concern. I've spelled out before you here some of the different areas that we typically evaluate when someone comes with a cognitive concern.

(06:07): Motor skills are part of cognition and refer to things like strength, speed and dexterity of movement. When I say motor examination, that really refers to all of the skills of movement, including things like the strength, speed, and dexterity of your movements, broad motor abilities, like your balance and gait, as well as the fine motor skills that might be necessary for things like writing, typing, or other fine fingertip coordination tasks.

(06:28): Visual spatial skills include not only your visual acuity and making sure that you have an adequate field of vision, but also your ability to put together the information coming from your eyes to make sense of what you're seeing. So that includes things like the ability to recognize an object that's in your field of view or recognize the faces of people that you know well, and it can also refer to your ability to judge relationships in space, like where you are relative to a doorway you're trying to walk through, or how to turn the steering wheel of your car to parallel park. And then, finally, some of the high-level spatial skills that are required for things like design abilities, drawing, assembly, or putting things together, those all fall under that visual spatial domain.

(07:20): Cognition includes language skills, such as word retrieval and the ability to express yourself. The language skills that we often assess include the ability to find words or retrieve the words you need to express your ideas in a fluent and efficient manner. Also, of course, the comprehension of what others are saying to you or what you might be reading, and your written language abilities, like spelling and grammar.

(07:41): As our brain puts information together from these basic function areas, like visual-spatial skills, language skill, into higher level abilities, like problem solving, multitasking, things like that, then we start to think about how the different areas of the brain are connected or integrated. And problems with the connections or integration of multiple brain areas often show up as information processing speed problems. In other words, you might be able to solve problems, but it's just not happening as quickly or efficiently as you might like.

(08:21): There are two different kinds of memory:  working memory and recent memory.  As we move up the hierarchy of complication or complicated cognitive abilities, we start to talk about memory. There are different kinds of memory, and it's helpful to break these down a little bit because it makes it easier to talk about the problems that you might experience in daily life.

(08:43): Working memory refers to the kind of memory you use when you just want to hold something in mind for a little while. It's not something you're planning on remembering for a long time, but you need to hold it in mind while you're doing something else. When somebody, your spouse, for instance, asks you to go downstairs and get something from the basement, as you're going downstairs, you're holding in mind what it was you were going to get from the basement, and hopefully you don't get distracted by changing over the laundry, and then look around and think, what was I coming in here for? That kind of problem, which is entirely normal and all too common for many of us, is a failure of working memory, and it relates to a set of brain areas which are shown in this figure on your slide. That includes areas of what we call the frontal lobes of the brain, and also areas of the parietal lobes of the brain, which are connected by a complex network of fibers.

(09:44): Information loops around in these circuits while we hold it in mind or while we try to manipulate it and think about it. For example, if you have to multitask, say I give you my phone number and you need to open up the contacts in your phone and create a new contact for me, and then enter the number in. All the while you're going through the steps, you're also trying to hold that phone number in mind. That kind of multitasking will light up your working memory brain areas just like you see in this figure on the screen.

(10:16): Recent memory, on the other hand is the kind of memory you use when you want to learn something new that you hope to retain over time. It might be the kind of memory you use if you are sitting and talking with your doctor and they're laying out treatment options for you or telling you what to expect over the next several weeks. It might be the kind of memory you use when you're reading a book, and you put it down and pick it up the next day. You want to remember where you were in that book. That kind of memory storage over time, in the recent past, is what we call recent memory.

(10:52): Making a memory involves encoding information, storing it in the brain, and the ability to retrieve it when needed.  It's helpful to think about the fact that, to make a good memory, there are three steps you need to take. The first step has kind of a fancy neurocognitive word we call “encoding”, which is really just attention. It's the ability to bring information into the memory system. And you have to be able to focus and process the information as quickly as it's coming at you. I'm talking kind of quickly now, and it may be that your ability to process the words I'm using, stay focused on what I'm saying, avoid distractions that might be going on in your home, all of that work together is the encoding process, and doing a good job of encoding is the critical front door for making a new memory.

(11:36): The second step is storage; storage of information is accomplished by this flashing structure that you see on the screen, the “hippocampus”. That's a critical memory storage area. And information that is encoded efficiently then flows into the hippocampus, which organizes information for storage and memory. It's kind of a mental filing cabinet if you will. The memories don't reside there, but all of the indexing of your memory, when it happened, who you were with, where you were, the other related information, is all bound together by the hippocampus.

(12:14): The third step is retrieval, the ability to come up with information later on. When you get home and your family member asks you, "What did the doctor tell you?" Or you pick up that book the next day and think, “Wait a minute, who was this character?"; that kind of information requires you to search back through your mental filing cabinet, identify the specific detail you're looking for, and pull it up when you want it.

(12:40): A failure of memory in your everyday life can happen because of a failure at any one of those three steps. And in an evaluation, when somebody is telling me they're having a memory problem, separating out the memory process into these three steps is something that we try to do with our testing.

(13:00): Studies in breast cancer have found that chemotherapy can affect the size of the hippocampus in the brain, which correlated with poorer memory. The reason that this is relevant, all of this detail, is that brain structures are differently affected by chemotherapy. For example, this picture that I have in front of you here has circled on it, that brain area I mentioned just a minute ago, the hippocampus. This study that I've referenced on this page, looks at differences in the brain area that circled, the hippocampus, between women who were, versus those who were not, treated with chemotherapy for breast cancer.

(13:44): They found a smaller size of the hippocampus in those who were treated with breast cancer, and the degree of change in that size or the degree of limitation in the size of the hippocampus, correlated with poorer memory scores, strongly suggesting that damage to the structure might be a problem associated with chemotherapy that relates directly to the memory problems that people experience.

(14:17): Attention and processing speed are often affected by chemotherapy and bone marrow transplant.  We talk about higher level cognitive abilities, and attention and processing speed are two of those abilities that really depend heavily on widespread networks of brain connections. When we talk about attention, we think about your ability to stay focused over time, your ability to deal with more than one thing at a time by dividing your attention between something you're really focused on, and perhaps something that you're aware of, but know that doesn't need all of your focus at the moment. And then the ability to shift your attention, to go back and forth between those two things efficiently.

(14:58): We see that speed of processing, which can often be affected by problems related to chemotherapy or bone marrow transplant, is really dependent on the efficiency of connections between brain areas and can often cause problems when you have to shift gears or deal with more than one thing at a time. The image that I've shown you here is from a type of MRI scan of the brain which highlights the fibers of connections and shows them in different colors relating to the direction in which they are oriented.

(15:37): The term executive functions refers to a collection of abilities that are at the highest level of cognitive function. Those include abilities such as initiation or the capacity to start working on something, your get up and go, if you will. That includes reasoning or the ability to generate strategies, test them out and solve the new problem. It includes mental flexibility. That is your ability to switch between competing tasks and come up with novel solutions, organization and sequencing of activities which are necessary for planning, as well as inhibition, that is, knowing when it's time to stop doing something that's inappropriate or is no longer working.

(16:33): Finally, skills such as insight or the ability to accurately perceive one's own performance, and judgment, the ability to make decisions that are aligned with your values, those abilities also fall under this heading of executive functions, and are of course things that we try to assess carefully in our evaluations, because problems with organization, problems with sequencing, problems with mental flexibility are often the kinds of issues that people notice after treatment.

(17:12): Different methods are used to assess different types of cognitive abilities. As I've been pointing out, we're assessing all of these different cognitive abilities using different kinds of tests. Those are methods that we use to try to understand what brain areas might be affected, how those brain areas are related to a person's experience in their daily life, and ultimately, what might be causing the problems that are experiencing?

(17:40): We know that certain brain areas may be particularly at risk in chemotherapy, such as the hippocampus, and we also know that the fibers that connect widespread brain areas seem to be more vulnerable to disruption than a lot of other functions. That means that the problems show up in issues of attention, processing speed, word retrieval, and those executive functions we've been talking about most commonly. We know from research that the brain areas or the brain tissues connecting networks within the brain are affected by chemotherapy.

(18:25): This slide that I'm showing you here on the right, highlights some of the fiber connections in the brain that were studied by a group based at Memorial Sloan Kettering Cancer Center in New York. The areas in orange are areas that connect brain areas across from one side to the other, from the left to the right side, and areas in green are connecting brain areas within a hemisphere. They highlighted these areas and studied the integrity or how reliable the connections were, on a physical basis, after people receiving bone marrow transplant went through induction chemotherapy. Those studies showed that there was a significant decrease in the integrity of those connections that also correlated with how well people did on cognitive tests of those abilities, such as attention, processing speed, and executive function.

(19:29): These, and similar studies, have shown us that ‘yes’, there are changes in the structure of the brain that follow directly after chemotherapy, and those structural changes relate to cognitive abilities. We also know from other kinds of research that uses functional brain imaging, in other words, techniques that allow us to see what parts of the brain are active while people are doing some kind of task, like trying to hold information in mind and their working memory, have also shown us that chemotherapy and other similar treatments associated with bone marrow transplant can affect the functional activity of those brain areas.

(20:15): In this study, the slide that you're looking at on the right here looked at a pair of twins, 60-year-old women, while they did a working-memory task, kind of like that holding the phone number in mind example that I gave you.

(20:33): Just for the purposes of orientation, we're looking down on the brain from above, and the front of the brain is at the top of the picture here. Remember how we talked about working memory depending on the frontal lobes and their connection to the parietal lobes? What you can see is that those areas are highlighted in orange, showing that there is a lot of activity going on in the frontal lobes and parietal lobes while these two people are trying to do a similar task, the same task, rather. One of these twins had cancer and had undergone chemotherapy. The other one had not. I'll give you a second to think about which brain you think was the twin who had cancer, the left or the right.

(21:25): In this case, the patient who had cancer and chemotherapy is represented on the left side of the screen might surprise you a little bit, as it looks pretty clear that there's more brain activity going on in that left picture. And that's true, there was a statistically significant difference in brain activity between the twins, with greater activation seen in the person who had undergone chemotherapy for breast cancer. One of the reasons thought to be at play here is that we're seeing potentially compensatory activity for a brain that is not operating as efficiently. In other words, the twin who is doing more work, working harder, is showing broader brain activity. These two women scored at the same level on the working memory task, but clearly there's a different level of effort going in for the twin on the left.

(22:29): Often, after chemotherapy, patients are able to do most of what they want to do, but it is harder than usual to do it.  I think that this helps to capture the experience a lot of people have with chemotherapy and cognitive problems, is that they're able to do most of what they want to, but it feels like it's much harder to do so. The people around you might not really feel like you've had a substantial change in your functioning, but you feel it and it feels different inside. This kind of functional brain activity type of study helps us to understand what might be going on here.

(23:02): One of the big questions about chemotherapy and its toxicity to the brain is why it seems to affect some people more than others. The reality is that there are a lot of factors that we don't understand, but there have been some consistent issues that are shown to play a role.

(23:24): For example, in this study from the Moffitt Cancer Center in Florida, doctors identified factors that increase risk of brain health problems in individuals. Those might be things like having had a brain disorder in the past or having had diabetes, hypertension, or heart disease, which may increase the risk for blood vessel problems in your brain, as well as a number of factors related to the person's illness for which they had a bone marrow transplant, how long they were hospitalized, whether they had other kinds of toxicities, whether it was a autologous or allergenic transplant, meaning whether your transplant came from an external donor or whether it was an auto transplant. And they put those factors together, identifying people who were potentially at high risk for cognitive problems versus those who were at lower risk by virtue of these risk factors.

All of those folks completed neuropsychological assessments prior to their bone marrow transplant, and then again at six months and 12 months after transplant. They found that the cumulative clinical risk, the addition of these different factors did relate to worse performance on tests of executive function that were present at baseline.

(24:56): You can see these two lines are different at baseline with a high-risk group having a lower score, as well as at six months after transplant. And then also, memory was shown to have a difference at six months and 12 months after transplant. A number of these issues, how many of these different factors are present in your particular situation, might contribute to whether or not you're likely to experience a problem, even before you undergo transplant or after you've gone through that treatment.

(25:35): Inflammatory reactions in the body seem to have a negative impact on thinking. Now, this slide is a little bit complicated, but what I want you to take away from it is that some inflammatory reactions in the body seem to have negative consequences for thinking. In this figure, you're looking at two different markers of how much inflammation or immune system activity is found in the blood, something called interleukin six on the left and tumor necrosis factor alpha on the right. Those are the left and right graphs that you're seeing there.

(26:13): The names aren't important, but what you can see is that people who have bigger increases of inflammation during treatment, in other words, if the bone marrow transplant causes your body to release a lot of these inflammation chemicals, those are people shown in the red line, they have poorer cognitive performance than those who have less inflammation shown in the green line. Okay? The idea is that these inflammatory reactions, or signs of the body's response to the toxicity of treatment that can be caused by the disease itself, which causes a lot of inflammatory reactions in our body, or also as a side effect of treatment, the important factor here is that future research is trying to understand how to manage these inflammatory reactions to minimize the toxicity of the treatment while also not interfering with its effectiveness. Again, I don't need you to understand the science, but what I want you to take away is that it helps us to understand what might be driving some of these changes at an individual level, and give us some places where we can potentially step in and try to correct the problem at the level of blood chemistry that helps to improve brain function.

(27:34): Most chemotherapy-related cognitive side effects seem to be potentially reversible or temporary. I've talked a lot about unsettling signs of brain issues related to these treatments and the conditions underlying them, but there is also some good news. First, I want to say that probably the highest on the list of positive signs is that the majority of chemotherapy-related cognitive side effects seem to be potentially reversible or temporary. It's been demonstrated, in studies that follow people over time, not only that function improves, but some very careful and creative studies have shown us that there are also improvements in the underlying brain structure.

(28:18): The image I have for you here in the graph is somewhat complicated, but this is a picture from a long-term study that followed people who'd been treated for breast cancer for up to five years. What they did is a special kind of scan of the brain to look at the strength of fiber connections between different areas. Remember that study I showed you earlier which demonstrated a reduction in that integrity took place after induction therapy for bone marrow transplant? This study found the same thing, and you can see it in the graphs. If you look at the second bar in each of these four graphs, you'll see that it's lower, and that represents the integrity of the different fiber bundles that are pointed to in different parts of the brain. That second bar was a measurement of integrity taken at about one-year post-chemotherapy treatment. But look at time three. That shows an improvement of return to baseline at three to four years post-treatment. Not only that, but the relationships or changes in integrity of these connections were shown to relate to cognitive functions, specifically processing speed and recent memory.

(29:54): So that study is informative, but it's only in people with breast cancer. This study shows that some similar findings have been found in bone marrow transplant survivors. This study followed almost a hundred bone marrow transplant survivors up to five years after transplant. In the initial study, they found that there were significant improvements in most domains over the first year after treatment. That's the left- most of these graphs on the slide. It shows you two different tests, a test of memory in the circles and word finding in the squares. Those changes were then followed over multiple years, as you can see in the graphs to the right, that followed the same people up to five years after undergoing transplant.

(30:57): I must note there was a significant percentage of the patients, up to 40% on some tests, who still had scores below average at the five-year time point.  It’s not accurate to say there are no long-term problems, but it is the case that even some of those with longer term low scores continued to have improvements over the follow-up period of time.

(31:28): It’s also helpful to remember that, generally speaking, the kinds of cognitive problems we see after chemotherapy tend to be on the milder side. When people experience severe cognitive problems that persist for a long time after chemotherapy has been completed, it's possibly the case that what you're seeing is not necessarily related to chemotherapy but could represent another problem or another issue that needs to be evaluated or addressed by your doctor. It's also important to recognize that it's only a subset of individuals who experience these problems. I suspect that most of you listening to this talk are here because you either have experienced these problems, have been a caregiver or know someone who's experienced these problems, or concerns that you might experience those problems.

(32:26): As I mentioned earlier, we don't know all of the individual factors that account for who does and who does not have those problems, but there are a number of factors that you can control that can improve how your brain is working. And those include some obvious things like getting good sleep, stress management, dealing with pain related problems, which can of course distract you and interfere with cognition, and then using a variety of other steps including lifestyle related issues like mental stimulation and cognitive strategies to improve those functions.

(33:05): There are medications and non-medical treatments available to treat cognitive problems following chemotherapy. That's a way to transition and talk a little bit about what can be done to help these cognitive issues when they do occur. There are medications that have been used primarily in other neurologic disorders, such as Alzheimer's disease and other types of dementia, that have been tried as treatments for people experiencing cognitive problems after chemotherapy. There have been some mixed, very mild benefits from those medications. In particular, the use of a medication called memantine has been shown to have some mild protective effects if someone needs to have radiation to their brain. And so many doctors who deliver radiation to the brain, radiation oncologists, may consider prescribing memantine prior to and during the treatment to try to protect some of the brain cells.

(34:10): Medications used to treat attention deficit disorder are sometimes helpful to treat cognitive problems after chemotherapy and transplant. There are also, more commonly, medications that are used to enhance attention like Ritalin, Provigil, Adderall, and other medications used in attention deficit disorder. Those have been trialed to reduce fatigue and attention problems, particularly in patients with brain cancer or chemotherapy related cognitive concerns, with mixed effects as well. And neuropsychological evaluation can often be helpful in deciding whose pattern suggests they might really benefit from that kind of treatment.

(34:48): Cognitive rehabilitation is a non-medical intervention that can help with cognitive problems. There are also a number of non-medical treatments for cognitive problems, particularly what we call cognitive rehabilitation, which is essentially two categories of treatment. The most effective are using compensatory strategies to overcome a cognitive limitation and still achieve your goals. These are typically worked on with specialists such as speech therapists or occupational therapy providers who can help you to integrate these kinds of strategies into your daily life and prevent an attention or memory problems from keeping you from doing what it is you want to be doing.

(35:32): Computerized brain training programs can help keep your brain active, but no more so than engaging in any other brain-stimulating activity. There are also cognitive stimulation types of approaches that you might think of as brain exercise, computerized brain training. There are many packages out there or websites available that offer this. And I often get asked whether or not this really works.

I think the way we conceive of brain training in a generic basis is that it is an important part of staying mentally active, but it's not special in that using a computerized brain training program is not necessarily going to do more for you than getting engaged or involved in some other mentally stimulating type of activities. We know that you can get better at the tasks you're doing, but whether or not that translates to real world changes is a little less clear.

(36:25): Of course, this has become big business over the years. This is just a graph showing, on the left, the growth of the use of these kinds of brain training games in the early part of this century and a webpage showing that some of the claims of these companies have been outside of what's been shown in terms of science behind their effectiveness. So do be aware of what you're spending your money on and ask your doctor for suggestions about those.

(36:57): Perhaps the most important piece of brain health is physical exercise, which we know is important to promote growth of new nerve cells even in the adult brain, to remove some of those inflammatory markers in the blood, improve the blood supply to the brain, and promote overall brain health through those mechanisms. Of course, if you're going through treatment for a serious medical condition, it's important to have a good sense of the type of exercise that's safe and appropriate for you. But in general, we want you to be doing aerobic exercises, such as a walking program.

(37:35): This is a graph from a study showing two groups of people who engaged in walking as they aged. Actually, the group who represent the blue line were engaged in a walking program, the group representing the red line, were spending the same amount of time in a program that only emphasized stretching and did not elevate their heart rate.

(37:57): The size of that memory structure I've mentioned, the hippocampus, was measured over a one-year period, and what they found is those engaging in the walking program had actual increase in the size of that structure, whereas those who were doing just the stretching had the normal age-related change in the size of their hippocampus over that one year. We know that physical exercise improves brain structure.

(38:27): As we go forward, there are new therapies on the forefront that are trying to take what we've learned about the science of chemo brain and turn it into treatments, do things like preventing the impact of those inflammatory markers on brain health, identifying and managing the modifiable contributors to cognitive functions that we've talked about and expanding the kinds of therapies that are potentially available.

(38:53): This is a graph or table that shows some of the ongoing clinical trials that are looking at specific types of medical agents and additional non-medical trials. Again, obviously there's too much detail here to make sense of.

(39:08): My point is that there's a number of different kinds of approaches that are using things like cognitive rehabilitation, electrical stimulation of the brain, stress management, exercise, and alternative therapies to try to address these problems, and there's promise and hope for the future that we'll get better at providing options for dealing with these cognitive issues.

(39:31): Summary of presentation. To summarize, there are plenty of reasons to believe that chemotherapy can affect the brain through a mechanism of toxicity, and that there are also other factors that likely contribute to cognitive problems after bone marrow transplant. The primary areas of difficulty include attention, memory, processing speed, and executive function. Fortunately, many of these problems seem to be relatively mild, and there is the potential for improvement and recovery over time, as well as options for treatment and support.

(40:05): A neuropsychological evaluation is a good starting point to understand the nature of your individual problem and identify techniques that might be helpful for you. And those strategies could be as simple as compensatory strategies all the way to medications. I'll stop here, and I am happy to take questions through the chat. And I'll allow the moderator to take over.

Question & Answer Session

(40:32): Lynne Spina: Thank you, Dr. Parsons, for your excellent presentation. Our first question is, "I had a stem cell transplant four years ago and a heavy course of steroids for GVHD two years ago. I am still on Tacro (Tacrolimus) and other drugs. I am also in my mid-seventies. I feel like my cognitive ability is much worse recently. Is this likely just aging or also chemo related?

(41:03): Dr. Michael Parsons: Yeah, that's such a complicated situation. As you're pointing out, it's rarely the case when you're going through a bone marrow transplant that it's just the chemotherapy and the bone marrow transplant that you're dealing with, and of course, the underlying disease itself that you're being treated for can take its own course.

(41:23): What you're describing is probably a combination effect of the multiple factors that you're dealing with. I didn't talk about graft-versus-host disease earlier, and of course it's hugely varied for people who experience it, particularly, obviously, after an allogeneic type of bone marrow transplant.

(41:46): Graft versus host disease can also cause a variety of inflammatory reactions in the body, which can sort of perpetuate some of the cognitive problems, keep them going for longer, though it's not necessarily the case that that's causing damage to the brain per se. It's also usually the case that graft-versus -host disease causes a lot of really problematic symptoms that serve as additional distractions when you're trying to concentrate. They may also disrupt your sleep, require you to take additional medications to suppress those side effects, and each of those can have kind of a spiraling effect on cognition.

(42:30): Then of course, the miracle of bone marrow transplant that you have gone through, has the advantageous effect that you get to enjoy the aging process, right? That's why we're all here because we're survivors of this experience. And that is the goal, but it also means that normal aging will take place. In your seventies, some change in memory concentration and so forth is a normal evolution. But really, a neuropsychological evaluation would be a great way to explain some of the problems you're experiencing, give you some answers about what might be going on for you, and perhaps more importantly, give you some strategies to try to help you deal with those problems on a day-to-day basis.

(43:20): Lynne Spina: Somewhat related to this, this person asks, "Is there an increased risk of getting Alzheimer's disease or mild cognitive impairment after transplant?"

(43:35): Dr. Michael Parsons: That question entails an area of intensive study occurring now in related medical fields related. The short answer is we don't know. There are two lines of research that I'll tell you about. One line suggests that the experience of chemotherapy treatment might take someone who already has a risk for Alzheimer's disease and accelerate it. That's not been proven and is a hypothesis that's currently under study.

(44:13): There are also published studies showing that at a population level, there seems to be a lower rate of dementia in people who have a history of cancer. This is not understood at an individual level. Some researchers feel it might just be a statistical anomaly in the way these studies are conducted. Again, the short answer is we don't know; we may have an answer in five to ten years.

(44:46): In the meantime, I think the important thing is if you have a concerning level problem with cognition or you have a family history that worries you as a risk for Alzheimer's disease, talk to your oncologist and your primary care doctor. They can refer you for an evaluation at an institution that is convenient to you as well as to the proper medical individual to give you the information you deserve. We'll talk through all the specifics of your history, assess what's happening in your brain function and give you feedback so that we see where you currently are and then monitor you over time to show any progression. So, great question; I'm sorry that I don't have a better answer for you.

(45:29): Lynne Spina: Thank you. This next question is from a person who wants to return to work but doesn't feel like she's ready to mentally process tasks or verbally communicate well. What therapy or help is there for her?

(45:46): Dr. Michael Parsons: I hear about this situation frequently from people who are survivors of bone marrow transplant and other chemotherapy treatments. It's often one where we involve therapists who work on these cognitive strategies. Ideally, we start with an evaluation that identifies your strengths and weaknesses and gives us some ideas of what to work on, and then we would have you work with a cognitive rehabilitation therapist as you transition back to work, working on both some strategies that can help support your problem-solving your memory so you can keep track of everything you've got going on, stay on top of all your tasks, and then work with you as you continue to get more and more involved, back in your job, perhaps on a weekly basis, getting feedback and specific examples of situations you might be dealing with to try to help you strategize and implement approaches that will make you successful. I think that situation is one that is perfect for an outpatient cognitive rehabilitation specialist.

(47:03): Lynne Spina: Great to know. This next person says, "I frequently cannot find the word I want, and I am struggling. Someone else will supply it for me. Should I try to remember the harder word for myself or should I just thank the person and continue on?"

(47:24): Dr. Michael Parsons: I hear that challenge from both sides, both from the person who's struggling to find the word, and often from their caregiver, friend, and/or family member, who is usually the one supplying the word. “Should I give them the word, or should I let them keep searching for it?” First of all, there's no reason to believe that not coming up with that word is doing your brain harm. So if you are getting the word filled in for you and there's that sense of relief, it's perfectly fine to just take it and move on. If you're the one supplying the word, you're not harming your loved one by helping them out in that situation.

(48:06): I think that the other side of that coin is that it is of value to work the brain areas that you're struggling with. Often, that involves doing some kind of cognitive stimulation that's relevant to the topic area you're struggling with, or again, working with a therapist on specific strategies or exercises. It's a balancing act between providing that stimulation and stopping somewhere short of the point of absolute frustration. At a certain point, the frustration itself will interfere with your ability to retrieve that word, and it's no longer productive to keep struggling. I think you need to find the sweet spot of searching, trying to express yourself, but getting yourself to a point of real stress or frustration.

(49:09): Lynne Spina: Thank you, Dr. Parsons. This next question may help with the previous question, What are the benefits of mindfulness in assisting with memory and recall?

(49:23): Dr. Michael Parsons: Mindfulness is a type of meditation-based approach. It goes beyond meditation and is a life-approach in which you increase your focus on the present moment, what you're doing in that moment, what your goals are, and try to minimize the kind of “chatter” that goes on in the back of our minds all the time. Mindfulness has been shown to have a beneficial effect on attention and concentration. As I was pointing out in one of the earlier slides, attention is the front door for the memory system. In fact, we know that practicing mindfulness can improve your encoding or taking new information into memory, thereby giving you more information to remember later.

(50:20): I think most of the research on mindfulness suggests that when you spend time meditating and trying to keep your mind in the present moment, noticing when you get distracted by an internal thought or external activity, and then gently bringing your mind back to the present moment without beating yourself up or engaging in a lot of negative self-talk about the fact you let your mind drift, repeatedly practicing mindfulness helps you to be more aware of when you're losing your attention  focus and bring it back onto the topic on which you want to be focused on. You then give more information to your memory system to remember later.

(51:12): Lynne Spina: Great, thank you. We're switching gears again to graft-versus-host disease (GVHD). Have GVHD medications been found to prolong cognitive or memory issues? When they are stopped, is there a similar improvement?

(51:29): Dr. Michael Parsons: I have to acknowledge that I am not as expert in terms of the specific graft versus host disease medications that are most commonly used. Often, those are in the steroid category, and they can be associated with cognitive problems. Whether the medication is associated with more cognitive problems than the symptom itself is a very individual call. In many cases, the graft versus host disease symptoms are so problematic that they contribute to a lot of cognitive problems in and of themselves, through distraction, sleep disruption, and other things as we were talking about before. In that situation, suppressing the GVHD symptom and reducing the distraction from it can actually improve your focus somewhat.

(52:25): However, you've got the other side of the coin, which is whether or not medication like steroids might increase your level of agitation, irritability, disrupt your sleep, and produce other problems of its own. It certainly is the case that many of those medications can have temporary effects on cognition that improve after they're taken off, especially if the graft versus host disease symptoms do not then resume.

(52:55): Lynne Spina: Thank you. Is there any research that shows that learning a new language or art therapy or music can assist in preventing cognitive impairments?

(53:09): Dr. Michael Parsons: That question gets back to the idea of cognitive stimulation as an important part of brain health. And the answer is absolutely; each of those activities is a very valid and potentially useful method of getting brain stimulation and keeping your brain active as you age or deal with a medical problem or its treatments. There is not, to my knowledge, great evidence to suggest that one of those activities is better than any other. My general guidance to people who are seeking out brain activity or brain exercise that might help them is to find something that you enjoy doing and engage in that activity. And by engage, I mean work with the material. Think about being in the driver's seat of that cognitive activity rather than being a passive recipient of information. If you're learning a new language, great. What I encourage you to do is speak the language, use the language, practice exercises that have you reading it, and working with that material rather than just getting it passively.

(54:30): If you're working in art therapy, the same thing exists. Engaging in a creative activity that provides a stimulation is the active ingredient in the mental stimulations that benefits cognition.

(54:46): Lynne Spina: Very interesting. And how about aromatherapy or essential oils? Do they help with brain function?

(54:55): Dr. Michael Parsons: I am not aware of any research demonstrating a relationship between aromatherapy and essential oils and brain function or structure. In general, that kind of approach is something that I suspect might have beneficial effects through its stress relieving components. Certainly, we know that carrying a high level of stress, particularly over a long period of time, has detrimental effects to cognition. So, if you find that aroma therapy or the essential oils help you relax, to reduce stress, that can have a beneficial effect on your focus, your processing speed, and your executive function.

(55:42): Lynne Spina: We have two related questions about chemo brain. I know you had mentioned these earlier in one of your slides, when you spoke about the significant improvements that have been studied over one year, five years; but these particular attendees are really asking specifically, “When will my chemo brain go away, and why am I having these extreme cognitive challenges four years post transplants?”

(56:16) Dr. Michael Parsons: That is certainly concerning, and I think it's right to be concerned if you feel like you're struggling with cognition that far down the road. We do know, as I had mentioned, that there are multiple different individual factors that play a role in how much cognitive difficulty someone might experience and how long it might go on.

(56:40): When we look at those graphs and studies, that's averaging together large groups of people. It's helpful to understand the trends, but it doesn't give information about what might be happening for you or what's happening to those people who are experiencing the longer-term issues or worsening concerns. That's a situation where I think it is perfectly valid, and perhaps important, to talk to your doctor about the problems you're having. It's that kind of question that I'm often asked to get involved in and evaluate a cognitive problem that someone's having to try to help determine, is this related to the chemo brain? Is this related to something else? Are there things that could be done or tested for that might be reversible?

(57:30): There are a number of those reversible causes of cognitive problems that need to be carefully considered. Or, in a worst-case scenario, is this a sign of something else going on that needs to be addressed, treated, or managed? If you're having long-term, persistent, or worsening cognitive problems, that's a reason to talk to your doctor, to see if there's something that can be done to help.

(58:02): Lynne Spina: Great. Good advice, Dr. Parson, on behalf of BMT InfoNet and our partners, I'd like to thank you for a very helpful presentation, and I thank you, the audience, for your excellent questions. Please contact BMT InfoNet if we can help you in any way.