Cognition after Transplant: Coping with Attention, Learning and Memory Issues

Cognition after Transplant: Coping with Attention, Learning and Memory Issues

July 12, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020

Presenter: Michael Parsons PhD, Neuropsychologist, Pappas Neuro-Oncology Center and Department of Psychiatry, Massachusetts General Hospital

Presentation is 43 minutes with 14 minutes of Q&A.            Download Speaker Slides  

Summary: High-dose chemotherapy and total body irradiation can change a person's ability to process and learn new information and focus attention after transplant, at least for a time. Learn some strategies for managing this post-transplant complication.

Highlights:

• Changes in the way the brain functions, sometimes called “chemobrain” or “chemofog”, is a common problem after high-dose chemotherapy and a stem cell transplant. 
• Changes in brain function after transplant are usually mild and temporary.
• A neuropsychological evaluation can help you better understand the exact nature of the problem you are experiencing and identify the right strategy to deal with it.

Key Points:

05:01     Cognitive function is the term used to describe the various functions of the brain including memory, concentration, speech and language skills, spatial abilities such as judging distances and executive functioning.

08:30     Chemotherapy can affect both short-term and long-term memory

11:33     Chemotherapy can affect the hippocampus, the part of the brain where memories are stored.

12:43     Networks that support attention in the brain can be damaged by chemotherapy and affect your ability to sustain attention, avoid distractions and rapidly process information.

13:50     Chemotherapy can interfere with executive functioning which includes reasoning, decision-making, higher-level attention, multi-tasking, planning, initiative and impulse control.

15:46     Cancer, itself, can affect brain function.

21:39     Risk factors for developing cognitive problems after chemotherapy and a stem cell transplant include prior brain problems, type of transplant, length of hospitalization during transplant, age, high blood pressure, diabetes, heart disease and toxicity of the treatment.

31:34     Cognitive rehabilitation can provide patients with skills to function well despite cognitive problems.

34:13     Computer brain games designed to help cognitive function are no better than other brain stimulating activities such as reading, learning to do a new task, etc.

36:53     Physical exercise is the single most powerful thing you can do to maintain brain health after transplant.

Transcript of Presentation

00:00     [Moderator] Welcome to the workshop, Cognition after Transplant: Coping with Attention, Learning and Memory Issues. My name is Mary Clare Bietila, and I will be your moderator today.

It is my pleasure to introduce you to today's speaker, Dr. Michael Parsons. Dr. Parsons is an Assistant Professor at Harvard Medical School and a neuropsychologist at Massachusetts General Hospital-Pappas Neuro-Oncology Center, where he specializes in cancer and cognition. His research uses cognitive assessment and brain imaging techniques to understand how cancer and chemotherapy affect neural systems, with the goal of developing treatment options for these problems. Please, join me in welcoming Dr. Parsons.

00:48     [Dr. Parsons] Thank you, Mary Clare. I trust that my voice is coming through loud and clear this afternoon. And please, let me know if there's any difficulty hearing me. It's definitely a little bit different to be giving this talk in this format. I certainly was looking forward to a conference here in Boston in May, where all of you folks, who are now online, would be able to come here and enjoy a lobster roll and maybe a stroll around the city. But as it is, I have made a promise that I will eat a lobster roll for every single attendee who is on the conference call today. So, thank you for your interest. And I'm looking forward to about a year's worth of eating lobster rolls in all of your honors.

Overview of Cognitive Function After Stem Cell or Bone Marrow Transplant

So, what we're going to be talking about today, as Mary Clare mentioned, is cognition and the issues that often occur with cognitive function for people who are going through bone marrow transplant, and long-term for survivors of bone marrow transplant for years afterwards.

I want to start out by just acknowledging that in addition to my work at an academic medical center, I do consult to some organizations and professional companies that are manufacturing drugs and treatments for cancer. The goals today are to talk about the types of cognitive problems that bone marrow transplant survivors experience and give a better understanding of how those problems are related to different brain systems and networks.

I'll talk a bit about what a neuropsychological evaluation is. That's one of the main things I do professionally. And I'll try to explain how it might be helpful if someone is dealing with cognitive symptoms. I'll give you an introduction to the science or what we know about the nature and causes of cognitive problems after bone marrow transplant. And in the final section, I'll talk about practical approaches and treatments for dealing with cognitive problems.

More specifically, what we'll talk about with cognitive abilities are those cognitive functions that are most at risk and how they're related to the potential effect of treatments and diseases on brain structures that underlie those functions.

In addition, while a lot of what we're going to be talking about is chemotherapy, there are a lot of things going on when you're dealing with bone marrow transplants. So, while chemotherapy is often the main factor, we talk about causing these symptoms, there are other factors such as fatigue, stress, the direct effects of the diseases themselves that are also at play.

And then, finally, when it comes to dealing with problems, we'll talk about the various methods and techniques that are used to understand the symptoms themselves. And of course, to provide treatment for those.

How chemotherapy affects the brain

03:57  Now, in the past, and I'm not talking about that long in the past, say 20 years ago, there really wasn't that much discussion about cognitive symptoms or the possibility that chemotherapy, including the types that are typically used for bone marrow transplant, might have a negative effect on the brain. If you talked with your oncologist about the symptoms, you might have been told that there's a special barrier between the bloodstream and the brain called the blood brain barrier that is supposed to prevent the toxic chemotherapy agents from getting into the brain. So, it's not possible that those symptoms you're having could be a toxic effect.

04:39     Now, we know those things are not true. And it's really no longer a question of whether or not chemotherapy affects the brain, but we're now talking about how chemotherapy affects the brain, what brain structures are most at risk, and how those symptoms manifest in terms of cognitive abilities or difficulties.

Cognitive function encompasses all the skills of thought.

05:01     Now, it's probably important for me to talk a little bit about this word I've been using, cognitive. When I'm talking about cognitive functions, what I'm really describing here or referring to are all the skills of thought that are accomplished. That might include everything from memory and concentration, to speech, and language skills, to visual, or spatial abilities, such as judging distances and identifying things that you're seeing, to this general topic or area we call executive functions.

Executive functions are probably best thought of as an umbrella term that captures the highest level of cognitive abilities.

Chemotherapy can affect the people's cognitive skills differently

And we're going to go over these in more detail in just a minute. So, for now, just keep in mind that executive functions are those high-level cognitive abilities, the ones that really distinguish human cognition from many other species. So, when people talk about experience and chemo brain, they may have a variety of specific experiences that they talk about. And the reality is that not all of those different cognitive functions are affected equally by chemotherapy or bone marrow transplants.

Memory problems after chemotherapy

06:27     Even when people use the same term, for instance, talking about having a memory problem, they may mean very different things. When some people tell me, they're having a memory problem, what they mean is, "I went to do something, and I can't remember what it was." Which is a type of memory we call working memory or prospective memory. I'm going to come back to that in a minute. But other people mean that they're having more difficulty remembering a specific word or calling up a term such as a word finding difficulty. Or people might more often mean that they can't remember something that happened recently or was recently discussed, such as conversations at home or something the doctor told you at an appointment, that thing.

Chemotherapy can affect concentration 

07:14  Another common term or type of problem that people describe might fall under the heading of brain fog or chemo fog. And usually, by that, people are talking about issues with their concentration, how quickly they can process information, or high-level reasoning difficulties, having trouble thinking through something that you might need to decide for your job, or making some complex personal decision.

Neuropsychological evaluations can determine how brain function has been affected by chemotherapy.

07:46     Now, we try, in a neuropsychological evaluation, to break down those cognitive abilities into domains of function, domains that relate to the systems and structures within the brain. And then, a typical neuropsychological evaluation, I don't know if many of you have been through that, but you will be tested on a variety of different kinds of abilities, procedures. Much of it is question and answer, or some puzzle-solving, some memorization, questionnaires, a whole variety of procedures like that, to try to separate out the different abilities into the underlying brain networks that support them.

Chemotherapy can affect working memory – the ability to retain information long-term

08:30  So, let me give you some examples of what we're talking about here in areas. Working memory, that is, the ability to hold information in mind versus recent memory, which is the memory used for retaining information. And the brain pictures here show us that there are different structures that are involved in those two kinds of memory. So, when you're using your working memory, say your mental desktop, something that you want to hold in mind for just a moment while you go say into another room to fetch something you're thinking of, you're using these systems or brain areas that are highlighted in green here to connect to the frontal part of the brain to the parietal part of the brain, and the networks that support those.

Chemotherapy can affect recent memory – the ability to recall information you recently received.

09:20  Recent memory on the other hand, such as your ability to recall a story told yesterday, or something the doctor told you at your last appointment, depends on a set of brain areas that overlap somewhat with working memory., but then, feed into deeper parts of the brain. Perhaps you've heard of a structure called the hippocampus. It's part of the deep temporal lobe systems. It's colored purple on this picture in front of you. And it's absolutely critical for storing new information that you're learning. So, when you want to remember something over a longer period of time, your hippocampus and its connections to the other parts of brain must be working well.

Now, when you think about that recent memory process, there are multiple stages that take place as you're trying to learn new information. The first step, encoding, is really very much like attention. It's the part where you're bringing new information into your memory system. It requires that you focus on that information and process it like if someone is telling you something that you make sense of their words.

Once you've encoded a piece of information, it proceeds to your brain storage system. And that's where that brain area, the hippocampus, really plays a huge role.

And then, the third step of recent memory is the retrieval process. That's where people need to reach into their memory filing systems and pull out a specific bit of information, say in response to a question or something you want to relate to another person.

And memory, recent memory, can fail because of an issue at any one of these three steps. So, in an evaluation, we will try to break down the memory system into those three steps and understand which part of the process is giving the problem because that relates directly to the part of the brain system and structures that connect to it.

Chemotherapy can affect the hippocampus – the part of the brain that stores information

11:33     We're talking about that hippocampus, that critical memory area. There have been a variety of studies that shown us that the hippocampus is indeed vulnerable to the effects of chemotherapy. For instance, in this study, which was initially published in 2012, it was found that there was a relationship between levels of immune chemicals that are triggered by chemotherapy and the size or loss of size in the brain structure called the hippocampus. That's this little circled area here on your screen. Now, what's more is that hippocampal volume or the size of that structure, correlated with people scores on test of memory. That is, the smaller that structure was, the more trouble they had on the memory testing.  So, we know that the hippocampus, a critical area for that recent memory, can be affected by chemotherapy.

Networks that support attention in the brain can also be affected by chemotherapy

12:43  In addition, there are a variety of studies that have shown us that the networks that support attention in the brain, which is a very common part of the brain fog or chemo brain problem, are also vulnerable to the effects of chemotherapy. And this image on the screen shows you a special brain imaging that highlights the connections and this incredibly complex network of brain areas that are required to interact to efficiently sustain your attention, shift your attention between multiple tasks, avoid distractions, and then process information in a smooth and rapid way. Those abilities really require these connections to be intact and functioning well because any difficulties with connections will essentially operate as a short circuit, causing problems with information transmission and slowing down your information processing.

The frontal lobes can be affected by chemotherapy, causing problems with executive functioning.

13:50     Another area of the brain which I mentioned earlier are the frontal lobes, which are colored blue in this image in front of you. And the frontal lobes are critically important for these executive functions I mentioned a minute ago. It's probably best, as I said, to think of executive function as an umbrella term. Under which, we lump the highest level of cognitive abilities. Those abilities are really evolutionarily distinct from other animals and correlate with the development of the frontal lobes in humans. Those frontal lobes account for about half the volume of the brain in human beings. But in lower animals, are really not as large, or in some, not present at all.

Executive functions include reasoning, decision-making, higher-level attention, multi-tasking abilities, organization, planning initiative and impulse control.

14:47  So, the executive functions include abilities like reasoning, using judgment. That is, to make decisions, and also higher-level attention abilities, such just those that we need to do anything you might think of as multitasking. The executive functions also include art initiative, your motivation or ability to start something. And on the flip side, the executive functions are important in our ability to control impulses or decide when it's time to stop doing something. Perhaps something that it's no longer appropriate to be doing.

Executive functions are necessary for organization and planning because they encompass our big picture skills, the ability to see what the larger goals of the projects are. And then, prioritize your day-to-day activities to meet those big picture goals.

Chemotherapy and cancer, itself, can impact a wide area of the brain

15:46     So, the cognitive tests that we use in neuropsychological evaluations have demonstrated that there are multiple brain areas that seemed to be affected when people are experiencing chemotherapy-related cognitive problems. And what that tells us is that chemotherapy, or the disease-related issues that it's trying to treat, probably affect a widespread area of the brain. And that's consistent with the notion that it's a blood-borne toxin that is impacting the brain in a widespread way.

Now, it's also been shown that, as I said earlier, cancer itself can trigger a variety of bodily reactions such as inflammation that contribute to those widespread effects. And there appeared to be not only these widespread effects, but as we said, sensitivity of certain brain areas like the hippocampus to those toxicities.

I want to give you an example of what we understand about not only how the brain structures are affected by chemotherapy, but also some of the examples that have shown us how this process can be studied and how we can try to potentially begin to intervene and protect the brain from these toxins.

Studies show speed with which patients process information after transplant may be slower

17:22     So, this is an example of a study in which the investigators... this is a group at Memorial Sloan Kettering Cancer Center, examined white matter integrity. White matter in the brain are the connections of the brain. So, integrity of the white matter really relates to how tightly bundled the wires are essentially, the cables in your brain, that communicate information. They use a technique, a special MRI technique, to measure the integrity of those fiber bundles. And they measured those both before and then one year after stem cell transplant in 22 patients who had hematologic disorders and compared them to 10 healthy controls who did not have bone marrow transplant but were scanned at similar intervals.

And what they showed was that over that one-year period, there was a decrease in the integrity of the white matter regions, which are highlighted in this image in orange. Those areas, highlighted in orange, were found to have a decrease in integrity over that one-year period after stem cell transplant. The letters in your scan, you can't really see those, those are just pointing out specific fiber bundles in the brain. And more to the point, there were correlations and relationships between the integrity of those white matter tracks and the performance on a variety of cognitive test. Particularly those tests that were timed or really tapped into speed of processing. So, this is a way that brain imaging has shown us where in the brain we're seeing the biggest effects.

Now, in addition to brain imaging... or I'm sorry, structural brain imaging, there have also been studies of brain function using techniques such as PET, which is positron emission tomography, or functional MRI, which allow us to see the areas of the brain that are active when people are doing things. Now, the pictures you see on this slide shows you brain scans, brain activity scans, of two women who were twins. One of those twins had gone through cancer and chemotherapy, and her 60-year-old twin sister had not. They were both performing the same cognitive test, a test of working memory, that ability to hold things in mind. And what you can see is that there's more activity in the brain that's on the left side than there was on the right side. And you can see that areas of activity are similar, just more widespread in that last picture.

Remember earlier, we talked about the idea of the parietal lobes and the frontal lobes? Well, in this picture, you're looking down on the brain from above. And the front of the brain is at the top part of each picture. So, that's the frontal lobe activity of working memory. And behind it, that arching orange area is the parietal part of the activity. Now, which of these two scans do you think is the patient who had cancer and chemotherapy? You might be a little bit surprised, or perhaps not, to know that it's the image on the left, the one that's showing more activity.

 Now, it's important to understand that both of these women performed the same level on the working memory test. They were equivalent. But it seems like it took more work in terms of brain activity for the person who's on the left, the person who had been through chemotherapy. And that is very typical of what people tell me they experience after chemotherapy when they're having cognitive problems. "I can do okay." People can't really tell them having a problem. But it's just a lot more work. It's much more effort. And the brain activity studies have borne that experience out.

Risk factors for developing cognitive problems or “chemo brain” after transplant

21:39     So, one of the big puzzles that we've tried to understand is the variability in cognitive problems for people who have had bone marrow transplant and other treatments with chemotherapy. We don't know why it seems to affect some people more than others. The reality is there are a lot of factors that we don't understand yet. But there have been some consistent issues that seem to put some people more at risk for problems than others.

This graph you see in front of you came from a study that was done at Moffitt Cancer Center in Tampa where they followed 278 people who underwent stem cell transplant for hematologic disease and completed a neuropsych assessment both prior to that treatment, and then, at six months and 12 months later. And they looked at a variety of different factors that they thought might put some people more at risk than others.

The factors, as you can see here on the slide, are things like whether or not people already had a brain problem of some kind. Whether the transplant was allogeneic versus autologous? How long the patient was in the hospital after transplant? Whether they had other toxic reactions, what their age was. And other risk factors, such as high blood pressure, heart disease, diabetes, and other things we know can affect the brain.

And ultimately, they determined that each of these risk factors does play a role. And the lines you see on the screen divide the patients into two groups, one that had a low number of risk factors. Meaning, less than two of these factors were in the negative. And the lower line, showing those individuals who had more than two of those risk factors... or two or more, I'm sorry.

And not only did the greater cumulative risk predict poorer performance at baseline, but it also seemed to have a difference on the degree of recovery that people experienced the year after a stem cell transplant. And this was particularly seen on test that tapped into executive functions, those high-level abilities we've been talking about. So, it does appear that a variety of these factors play a role. And the more of these factors you have working against you, the more likely it seems that you may have cognitive symptoms or side effects.

Inflammation in the body has been associated with cognitive problems

24:23 In addition, in looking a little more detail into what are the mechanisms that cause this problem, it's been discovered that issues related to inflammation in the body, and this is something you may hear a lot about in your medical care or news, have an impact on cognition. Now, this slide is a little bit complicated. What I want you to take away from it is that these inflammatory reactions, particularly two different biomarkers studied in this experiment, something called interleukin 6. That's referring to the left graph. And tumor necrosis factor alpha is the inflammatory marker that's studied in the right graph. The names aren't important, but what you can see is that for the people who had larger increases in those inflammatory factors, those are the people pictured in the red lines.

They tended to have poor cognitive performance than those people who had less inflammation. Those are the green lines. The basic idea here is that these markers are signs of the body's reaction to the toxicity of the treatment. And also, to the toxicity of the disease. And future research that's ongoing now is trying to understand how we can prevent these kinds of inflammatory reactions in the body and minimize the toxicity of the treatment while not interfering with its effectiveness.

 So, I've thrown a lot of stuff at you there, some of which is not entirely wonderful, that some of those factors undoubtedly apply to many of you listening to this talk right now. And you might be thinking about your own experiences or risks, or concerns about cognition. I do want to say that there are some positive things to report from the science on chemo brain, however. I think we can all use some good news these days.

The effects of chemotherapy on the brain appear to be temporary, for most people.

26:43     Most importantly, the majority of chemotherapy-related side effects seem to be temporary. Now, that's been demonstrated by following people overtime after they received chemotherapy. And not only do people's abilities, functions improve, like on our test scores or in their daily lives. But some very careful and creative studies have shown us that there are improvements in underlying brain structure as well. So, this image is from a long-term study that followed patients after they received chemotherapy for up to five years. They scanned the brain to look at the strength of fiber connections.

Remember that study I showed you earlier which demonstrated a reduction in the fiber integrity or the tightness of bundling of our brain's cables? Well, this study found the same thing. And you can see it in the graphs. So, if you look at the graphs with the bars on them, the second bar in each of those four graphs, which represent four different fiber bundles in the brain, shows a decline from the first bar to the second bar. That's the decline in integrity of that fiber bundle one year after treatment.

But look at the third bar, the one that's marked T3. That shows an improvement of return to baseline by three to four years after treatment. And not only did the integrity of the white matter fiber bundles improve and recover back to baseline, but those improvements were also correlated with improvements in functioning, particularly those abilities we've been talking about such as processing speed and recent memory.

Now, the previous study I showed you just there was in breast cancer patients, but very similar findings have been shown in the people who are recovered from bone marrow transplants. In this particular example, this was a study that followed almost a hundred bone marrow transplant survivors up to five years. And the initial study they published was from data from the first year, and that's in the left graph here. And what you can see is performance on two different tests.

 It's a test of memory that's marked with circles and a test of word finding that's marked with the little squares. What you can see is that scores on those tests dropped at about 90 days after transplant but improved at one year. And then, the right graphs followed the same people over as much as five years. And what they saw was that on all of the tests, that ability was maintained over that five-year period. And these slight increases or decreases on these two tests are not really meaningful.

They're not big enough to be a meaningful change over five years. But it was reassuring to see that these scores and abilities seemed to stabilize after that first year. Now, I do need to point out that up to 40% of people on at least some of the tests did have scores that were below average at the five-year time points. So, I don't want to imply that there are no long-term problems. But it is the case that even some of those with longer term low scores had improvements over the follow up time.

Now, we've seen that there are some positive outcomes despite the fact that the reality of chemo brain exists, and it's a problem that people experience. To summarize, it does seem to be a relatively speaking, mild problem. And when I say relative, we're comparing that to other neurologic injuries or dementias, or problems along those lines. And much of that does seem to recover overtime. Now, as I mentioned in the initial slide, it's not just chemotherapy that can affect cognition.

How to improve brain function after transplant

31:15     And when you start to think about what to do about these cognitive problems, I think that the first things to consider are those kinds of interventions that can be implemented in for anyone to improve their cognition. So, let's talk about things that can be done to improve cognition, both in the short- and long-term. So, there are a variety of interventions for chemotherapy-related cognitive impairment. And some of these include structured intervention such as cognitive rehabilitation.

Cognitive rehabilitation therapy after transplant

 31:54    Cognitive rehabilitation is a therapy usually practiced by speech therapists where you would work one-on-one with a therapist to try to improve your ability to perform some skill or ability. Usually, you would have some specific targets or things that you wanted to work on and make better in working with your therapist. You might try to improve your performance at organizing information for work or retaining information, learning people's names if you work in sales or something along those lines.

The therapists have a variety of strategies, techniques and tricks that they can teach you, or provide some strategies for compensatory mechanisms that will allow you to back up your own memory, or provide ways to reduce distractions and improve performance in that environment. And that success, when you do make improvements and are able to function while doing something that you may be struggling with, can have a positive effect on other cognitive abilities as well.

 Environmental modifications and behavioral strategies to improve brain function after transplant

33:05     The kinds of compensatory strategies that we might talk about in cognitive rehabilitation includes some that take advantage of associations between information that's difficult to recall, such as names, using things like face-name association strategies, which is one that's been used by waiters and waitresses for time immemorial. Or you might use more supportive strategies like technological devices, calendars, medication organizers, reminders, and alarms. You might make changes in the environment you're trying to work in or use techniques and strategies to enhance your attention to the thing you want to focus on.

What you can see from those kinds of strategies is we're not talking about rocket science here. We're talking about practical problem solving. But when it comes to addressing a specific difficulty, that problem solving has been shown to be the most effective means of being more successful to things you want to do.

Computer brain games are no better than other mentally stimulating activities in improving brain function after chemotherapy and transplant.

34:13     Now, there is this area of brain exercise that I'm sure many, if not all of you, have heard of at one time or another. And often, when I'm working with people who are trying to improve their cognition, this is the topic of conversation. So, just a minute on what we know about brain exercise, such as computerized brain games and so forth.

The principle that is at work here is that brain stimulation or cognitive engagement is an important part of maintaining brain health over the long term. And working that into your daily routine can take any of a number of different forms. Brain exercise programs like computerized brain training are one of those forms.

35:01 And certainly, if you're looking for ways to get mental stimulation into your daily routine and struggling, then brain exercise programs are perfectly reasonable way to do that. But that doesn't necessarily mean, and it has never been demonstrated, that they are any better than other mentally stimulating activities that you might find engaging. Whether that's being part of a book club or learning to play an instrument, or learning some other new information, all of those things provide that mental stimulation. In general, we think that activities that enhance association, build networks, those are the kinds of things that are really important for mental stimulation and maintaining brain health over the long term. We do know that when you practice those brain games, you will get better at the brain games. But it's not that clear that that improvement makes a meaningful impact on your ability to do things in your daily life that might be important to you.

 So, I like to say, buyer beware. These brain games are certainly a big business now. And the graph on the left there shows growth in the sales of these kinds of brain game activities early in the 21st century. And the figure on the right points out that one of the companies that marketed these brain games was fined several million dollars by the Federal Trade Commission for making claims about the ability of their brain games to improve cognitive function that were not backed up by science. So, if you're looking for a way to get brain stimulation, I think that these kinds of activities are perfectly reasonable. But don't feel that you need to be compelled or that you're somehow neglecting your brain health if that's not what you're doing.

Physical exercise is the most important thing you can do to improve brain health.

36:53     When it comes to maintaining brain health, probably the most evidence has been shown in studies, are physical exercise. Clearly, physical exercise is the single most powerful thing you can do to maintain your brain health. And it's been shown to promote the growth of new nerve cells, even in adults throughout the lifespan. It reduces some of those inflammatory chemicals we were talking about. It improves the health of the brain by improving blood supply, and also helps with other neural and cellular functions that promote overall brain health. It is important obviously to come up with an exercise program that's right for you. And that may involve talking with your doctor about what's right. But the general guideline for exercises, you want to be thinking about moderate aerobic exercise, such as you could get from a walking program, where you're elevating your heart rate a little bit, but not necessarily worrying about training for a marathon or anything like that. But if you're elevating your heart rate a little bit more days than not, you're probably getting most of the benefits of exercise.

This is an example of one of the studies that shows how exercise helps brain structure. This study talks back to our old friend, the hippocampus here. It's highlighted in yellow on the brain image you see. And they studied two groups of people, randomized people to either do a physical exercise program that was a walking program, four days a week or to do a stretching program that didn't elevate the heart rate in the same way as the walking program. And they measured the size of the hippocampus over a one-year period during which people participated in these exercise programs. And I think you can guess which line were the walkers and which line were the stretches.

38:54     What's interesting about this study is that the size of the hippocampus decreases as we age. Over a year, this is about the normal volume loss in hippocampus. But in the people who were exercising, they actually saw increased size of the hippocampus. And these individuals were people in their 60s. So, we're not talking about people whose brains are expected to be growing. But rather, they're promoting a growth of brain cells or at least increase in the size of an important memory structure by use of exercise.

39:30     So, as we think about where things go next, there are a variety of strategies that are being tried to prevent the pathology or damage from chemotherapy. There are also a variety of strategies that are being tried to reduce the body's inflammatory reactions, which seemed to play a role in potentially causing the cognitive and brain problems from chemotherapy. It's important to think about those contributors in daily life that you can modify or control, such as fatigue, stress, and other factors. And as we move forward, there are a variety of new therapeutic approaches that are being studied. Many of those are medication effects.

Medications are being studied for chemotherapy-related cognitive issues after transplant

40:20     And there are a number of medications that have been studied to try to help chemotherapy-related cognitive problems. Mostly, those are medications that enhance attention such as methylphenidate, which is also known as Ritalin. I've also heard recently that Wellbutrin is sometimes used to try to provide a low level of stimulation of the attention system, and also provide a little bit of boost to energy. This graph here shows you studies that are ongoing right now. Look at the effect of medications on chemo brain and in people receiving chemotherapy or other cancer treatments. And you don't need to know what all of these are other than to say, my point is that there are a lot of things going on in the medication domain to try to come up with effective treatments.

Non-medical interventions being studied to help brain function after transplant include cognitive rehabilitation, advanced neural stimulation, and exercise.

41:16     And in addition to medication, there are also non-medical approaches that are currently being studied to try to improve these effects. That can include everything from cognitive rehabilitation, which I discussed, to more advanced neural stimulation techniques, like this thing called transcranial direct current stimulation. Many of these studies also integrate physical exercise as part of the treatment approach. So, my hope is that this point out, there's a lot of things that are in the works. And moving forward, we hope that there are effective treatments that can help people even more actively promote recovery of cognitive function to transplant and chemotherapy.

Summary

So, to summarize, I think what we've covered here is that there are certainly reasons to believe that chemobrain is a real thing. And that not only is that contributing to brain function issues, but there are other factors and specific risk factors that may contribute to cognitive problems for some people, more than others.

 The areas of functioning that we've talked about as being most affected by the chemotherapy include attention, a memory processing speed and these executive functions. On the positive side, the relative size of these cognitive problems tends to be in the mild range for most people and seems to recover for most people overtime.

Now, treatments for cognitive problems are available, and neuropsychological evaluations can help you to understand the problem better and can directly relate to identifying the right strategy or approach for you to deal with these cognitive problems. Those strategies could be anything from medication treatment to compensatory strategies, to management of other factors involved in cognition.

 So, I'll stop there. I thank you all for your attention. And I hope that this information has been the thing you're interested in.

 43:30 I'm happy to have Mary Clare moderate some questions for us, if there are any.

Question and Answer Session

43:36     [Moderator] Yes, we have quite a few questions. Thank you so much, Dr. Parsons. That was an extraordinary presentation. Let's see. All right. So, Eliana asks our first question. "Is there any way to distinguish between transplant side effects and the onset of dementia?"

43:55     [Dr. Parsons] Yeah, that's a great question, Eliana. Obviously, because many transplant recipients are also in an age range where dementia is a concern, you are not alone in having this question. It can be difficult to distinguish because there isn't really a specific diagnostic test for dementia that can either prove it or rule it out. One of the things, the thing that I do most, a neuropsychological evaluation however, can be a very useful way to get to the bottom of that question. While it can't 100% rule out the possibility or rule it in, with a high degree of certainty, I can usually tell if the problem you're dealing with is more likely to be chemotherapy side effect or the more worrisome start of something progressive.

Furthermore, by doing an evaluation, what we're able to do is set a baseline that gives us a measurement of where different cognitive abilities are at a set point in time. And then, I can work with you or connect you with one of the therapists who works with me. And we can focus and target those problems and follow and monitor cognitive function overtime. And it's often following things overtime that is necessary to really determine the trajectory of the problem, which is an important part in distinguishing chemotherapy side effects from dementia. So, I think starting with a neuropsychological evaluation is a very direct and noninvasive way to try to get a better handle on that problem.

45:33     [Moderator] All right, wonderful. Our next question is from Gregory. "Can brain fog affect motivation?"

45:41     [Dr. Parsons] Absolutely. In at least two ways. So, one of the ways it relates to that concept of executive functions that I talked about earlier, one of the abilities that gets lumped under the executive function umbrella, is initiative, spontaneity or motivation, drive to do things. That ignition switch in our brain is in the frontal lobes. That's probably an oversimplification, but it depends on the frontal lobes. And if you're having losses, fiber integrity involving that, it can absolutely be reduced. So, one way is that direct cognitive effect.

The other way that motivation can be affected is secondarily through fatigue, which is of course very common experience for people after a bone marrow transplant. Fatigue simply stops your energy. So, you have an ignition switch problem, and you also have just a motor not getting running problem that can contribute to that. And finally, the stress of going through bone marrow transplant of facing a life-threatening disease and all of that, all that's entailed with that can also undermine motivation through the window of stress, even depression.

So, there are a number of potential relevant issues there. And there are a number of treatments that can help with motivation, initiative, fatigue and depression. So, if that's an experience that you're having, it's definitely one you want to talk to your doctor about because it's the last thing we want you to do, is survive bone marrow transplant to not be able to enjoy life afterwards. So, starting with those questions can lead to a little investigation that might really help.

47:33     [Moderator] Wonderful. Okay. Our next question is from Gerald. "How can you evaluate the stem cell transplant or chemo effects and cognitive loss if there's no testing before the transplant to get a baseline for the patient?"

47:49     [Dr. Parsons] Yeah, it's a difficult question. The reality is the majority of people receiving bone marrow transplant do not get any baseline evaluation prior to that. And in fact, even if you did, the issue is when you're going into bone marrow transplant, you're usually not feeling your best. You've already been dealing with a very serious medical issue for some time. And as I mentioned, the underlying diseases can lead to some of the same brain effects as the treatment itself.

So, the baseline evaluation would be nice if you want to isolate chemotherapy alone, but it's not everything. So, what we do is to compare your performance to some general benchmarks that relate to you in terms of your age. In some test performances, educational background is an important variable that affects our expected level of functioning. In other tests, your gender might have an influence on your expected level of functioning. And we look for a pattern to see where your abilities are at that baseline level or that expected level rather.

And where or what pattern of weaknesses we might see. And we look to see whether that pattern of strengths and weaknesses is typical of bone marrow transplant or chemotherapy-related side effects. Or whether it's more suggestive of another underlying problem or some other issues. And there are characteristic profiles of chemotherapy-related cognitive problems or other cognitive problems that a neuropsychologist can distinguish. So, it's not perfect by any means. It does not compare you to yourself.

And we're always taking into consideration the individual's experience of symptoms and their perspective, their observations about what's changed, because we know we didn't see you before. So, we look for your input on that. We look for family's input on that. We put that together with the pattern we see on your assessment. And then, we base our opinions and recommendations on that difference.

50:04     [Moderator] Okay. Our next question is from M. "A few years out of GvHD and dealing with healing a brain and eyes. Tacrolimus affects this person's clear thinking. What is the research and how long it takes the brain to heal from all the damage from treatments and medication?" And an additional question, "Does the systematic nervous system affect the whole? And does the brain heal like other organs over time?"

50:38     [Dr. Parsons] So, let me break that up a little bit. I think there are, as you may know, the central nervous system that refers to the brain and spinal cord, and the peripheral nervous system. Those are the nerves that go out to the toes and fingers, and throughout our body, outside the spinal cord. And I think what you're asking about is whether the toxicity affects the central nervous system and the peripheral nervous system in the same way. The answer to that is no.

There are many peripheral nervous system symptoms that people can experience after chemotherapy. Most of which fall into the heading of neuropathy, which would usually be experienced as a numbing or tingling in toes and fingers. Sometimes, painful burning sensations. And those seem to be pretty independent of central nervous system problems like memory and other cognitive issues. In other words, people can have peripheral neuropathy without experiencing any cognitive problems whatsoever and vice-versa.

Now, the agent you mentioned, tacrolimus, is one of many chemotherapy agents. And there are so many that are often used in combination that it's hard to disentangle which agents might affect which systems more or less. What we do know is that most of those agents do have the potential for toxic side effects.

And the recovery that you asked about, does occur in the brain as it does in many other body systems? Maybe not quite as fast. As you saw from some of the studies, I presented some recovery. The majority of recovery seems to occur in the first year. But in the brain imaging studies that have looked at the integrity of white matter, those fiber bundles in the brain, we've seen recovery going up to three, four, even five years out after treatment. So, that recovery does occur, and it can take a long time.

52:47     [Moderator] Okay. Wendy asks the next question. "Can this lead or contribute to the risk for Alzheimer's disease?"

52:57     [Dr. Parsons] That is a very hot topic question, Wendy. There's a theory out there that chemotherapy can lead to an accelerated brain aging. In other words, that the slope of decline in brain function, some brain function, that is an unfortunate but very natural occurrence with aging, might be made steeper by having been exposed to chemotherapy at some point earlier in your life. That topic is under intense investigation right now. And the answer really isn't known.

One of the things that we're interested in, and this is a topic that's being studied at my institution, is whether, say risk factors like having a high degree of Alzheimer's disease in your family plus chemotherapy might then accelerate or increase your individual risk beyond what it would have been anyway. And we simply don't know the answer to that right now.

I think the important thing to take away is that if you know that you are already perhaps have a higher than average risk for Alzheimer's disease, say if both your parents had Alzheimer's disease or something like that, then the kinds of things that we would suggest you do to maintain and optimize brain health for that risk are exactly the same things as you would do to maintain and optimize brain health after chemotherapy. And those primarily consists of a healthy diet, physical exercise, mental stimulation, and controlling those things you can control that contribute to brain risks, such as high blood pressure, diabetes, high cholesterol, things like that. So, at this time, all we can tell you is, be proactive. Do the things that are within any of our control to optimize your brain health. And we are trying to best understand the relationship between chemotherapy and risk for dementia.

55:05     [Moderator] Okay. I think we're going to take one last question. And I'm actually going combine two because they're quite similar. Gregory and Karen both asked about medications that might be used after a transplant or as maintenance therapy, such as oral chemotherapy or immunotherapy, and how they have been shown or not shown to impact the brain.

55:32     [Dr. Parsons] Great question. So, the oral chemotherapy agents, if you're talking about truly what we call antineoplastic chemotherapies, that is, chemotherapies that kill dividing cells, do have the potential to promote toxic effects on the brain. And there are some differences and degree among the various many agents that are out there. Your oncologist probably would be the best one to tell you about what they know about risks of that specific medication. But as I said, the reality is since they're so often combined, it's hard to separate out which ones are the culprits.

We know from animal studies, looking at the effects of these different medications individually on cells and petri dishes, and so forth, that most of them are associated with some neurotoxic effects. Now, immunotherapies, the hot new topic in cancer treatment, seem to have a little bit better overall side effect profile, with the exception that there are some people who can have very negative immune reactions where your immune system attacks other body organs.

And although it's very rare, immune-mediated encephalitis or effect on the brain from your own immune system, can be one of those side effects. So, if you're on immune therapy and you develop some significant cognitive problems, you definitely want to talk to your doctor about that.

57:09     [Moderator] Thank you so much. We're going to end here. And on behalf of BMT InfoNet and our sponsors, I would like to thank Dr. Parsons for his very helpful remarks and wonderful, thorough presentation. And thank you to our audience for your excellent questions. We're sorry, we were not able to get to all of them today.