Cognitive Challenges after Transplant and CAR T-cell Therapy and Treatment Options

Transcript of Presentation

(00:01) [Michala O’Brien]: Speaker Introduction. Welcome to the workshop, Cognitive Challenges after Transplant and CAR T-cell Therapy and Treatment Options. It's my pleasure to introduce today's speaker, Dr. Zev Nakamura.

(00:11): Dr. Nakamura is a Psychiatrist and a Clinical Researcher at the University of North Carolina School of Medicine. He supervises a psycho-oncology training clinic that addresses cognitive and other neuropsychiatric concerns of cancer patients undergoing various cancer treatments.

(00:28): Dr. Nakamura's research involves evaluating patient-reported cognition outcomes, understanding how other psychosocial and biological variables impact cognition, and testing pharmacological and behavioral interventions to prevent or treat the cognitive consequences of cancer and cancer care. Please join me today in welcoming Dr. Nakamura.

 (00:55) [Dr. Zev Nakamura]: Overview of Talk. Thank you so much for having me. Today, there are a few main topics I'm hoping to cover. I’d first like to discuss how common it is for people who have received a bone marrow or stem cell transplant or CAR T-cell therapy (CAR-T) to experience cognitive side effects and long-term problems. I want to give people a sense of how long these cognitive difficulties last, how they might change over time, and discuss the degree to which they're reversible. I’ll conclude with the discussion of treatment options – including lifestyle modifications that anyone can and should do – to help maintain and improve their cognitive function.

(01:44): I want to start with a brief history about this area of research looking at cancer and cognition. While the very first report of cognitive problems related to cancer and cancer treatment was a paper published in the 1970s in the American Journal of Psychiatry, there was very little recognition or interest in this area for several decades. Things started to change in the 1990s when the breast cancer patient community started using the term ‘chemo brain’ to describe the cognitive side effects they were noticing. People started to look more in-depth about the types of cognitive problems that patients with cancer were experiencing and initially began their focus on chemotherapy. We didn't have our first study showing how these cognitive changes might evolve or change over time until 2004.  

(02:42): Over the last two decades, there has been an increased focus on this area, and we've learned that these cognitive problems are not just specific to chemotherapy but can occur with a wide range of cancer treatments, and perhaps even just from the cancer itself.

(03:05): When I refer to cognitive problems, I'm describing a wide collection of symptoms. Some things patients describe include difficulty finding the right word they're looking for, difficulty with multitasking, or difficulty completing complex tasks. This also includes a decline in concentration or focus, slower thought processing speeds, and difficulty planning or strategizing something that includes multiple steps within their daily life. 

(04:20): Memory is definitely an area of cognitive function that is impacted by cancer treatment as well, and is the most common problem that I hear patients describe. Specifically, patients will often say that their long-term memory is fine, but their short-term memory is substantially impacted. We might have time later to talk about what exactly that might mean.

(04:29):  Here is an image from an older research study observing two twins. These images are functional MRI scans which show, in color, how much brain activation is happening – or how hard the brain is working.  Row A shows the brain of a woman with cancer who is undergoing chemotherapy. Row B is the brain of her twin sister who hasn't had cancer and hasn't received cancer treatment.

(05:30):  As you move from left to right, you can see their brains and the amount of activation – or how hard they're working – as they are asked to do increasingly difficult cognitive tasks. The healthy sister in Row B displays the expected pattern; when the task is very easy, there's very little brain activation. As she's asked to do something progressively harder, she uses more brain power to complete the task.

(06:00): You see something very different in the sister with cancer. Even during the easiest version of the task, her brain is having to work quite hard. When you compare these MRI scans to cognitive function, things start to get interesting.

(06:25):  When these two sisters were asked how they felt about their cognitive function, there were massive differences. The sister with cancer said she was really struggling, and that fits with what the MRI scan showed. Though she did do worse than her healthy sister, it was only marginally worse. This is a very common pattern we see across cancers and across cancer treatments. While we can see an impact on cognitive function during testing, that impact is usually quite small, but the patient often feels that the impact to their cognition has been much greater than what the results tend to show. 

(07:17): In general, the cognitive changes – or cognitive decline – that occurs due to cancer treatment is usually subtle or small, but the effects can feel very large. The research shows that even small declines in brain function can have major impacts on the individual’s work abilities, and their emotional and social wellbeing. It might impact their ability or confidence to do important everyday tasks, like manage medications or pay bills. It may also increase the risk for long-term cognitive difficulties.

(08:06): Now, let’s look at how common these issues are, and how long they last. While the majority of research has focused on chemotherapy and the breast cancer population, we see a lot of consistency across cancers and cancer treatment. Regardless of the treatment, we find that if you evaluate a group of patients before they get treatment--chemotherapy, transplant, CAR-T-- about a third will experience decreased cognition compared to healthy people of similar age, race, and educational background.

(08:52): During the time they are receiving treatment, a higher percentage will report noticing cognitive impairment. These difficulties do improve in many people, but anywhere from 15-50% may experience these difficulties for years post treatment.

(09:17): On an individual level, we see quite a bit of variation, and I'm going to try to illustrate that with these plot graphs. These plot graphs are from a study observing about a thousand breast cancer patients, and the cognitive changes they experience over the course of chemotherapy. Again, these figures are looking at the breast cancer population because that is where most of the research has occurred. However, I'll turn my focus towards unique factors within patients who received a transplant and CAR-T cell therapy in just a moment.

(10:01): The patients receiving chemotherapy for breast cancer are yellow, and the healthy controls are blue.  Even during pre-treatments, the breast cancer group reported decreased cognitive function than their healthy peers, and after chemotherapy, they reported a substantial worsening. Following up six months later, on average, people reported doing better, but still not as well as they were prior to chemotherapy, and certainly not as well as the control group.

(10:52): What's interesting here is that if you pivot from average changes to looking at subgroups of people, you see a little bit of a different story.  This is focused on changes from pre- to post-chemo. And if you look at the chemotherapy group now, you can see that about 45% of people report a substantial or significant worsening in their cognitive function from pre- to post-chemotherapy. But on the other hand, actually more than half say that they've had no change, or maybe even that their cognitive function has improved. 

(11:40): Not every person is going to experience the same thing when they go through cancer treatment, but on average we see that people have a cognitive decline following some sort of aggressive cancer treatment, and then a rebounding of their function with time. Let’s focus on this idea of experiencing cognitive difficulties even before receiving cancer treatment.  

(12:22): About a third of all cancer patients studied, regardless of their diagnosis or treatment, demonstrated worse than expected cognition. Within the research, we have noticed some trends regarding who these people are. They tend to be people who have more advanced or aggressive cancers, and people who might have certain features like molecular or protein markers on their tumor.  

(12:51): In addressing why cancer would contribute to cognitive problems, the prevailing theory at this time is that people with more aggressive cancers have higher levels of inflammation. Those increased levels of inflammation are at least one important factor driving the cognitive problems. 

(13:18): Now, let’s discuss those who have received a bone marrow or stem cell transplant, and what side-effects they report in regards to their cognitive function. The first thing to acknowledge is that patients undergoing stem cell transplants have already received multiple courses of chemotherapy, and as we saw in the previous slides, chemotherapy alone affects cognitive function. When a person is admitted to the hospital for a transplant, they receive an additional regimen of chemotherapy to prepare them to receive the transplant. Many patients also undergo radiation, which might increase their risk for cognitive problems. There are also multiple medications that these patients receive that may be associated with cognitive problems, such as steroids and immunosuppressant medications. Patients who go through transplant are also at increased risk for a variety of infections, including certain viruses that can directly impact the brain. 

(14:47): While today we are primarily focusing on long-term cognitive difficulties, a quarter of transplant patients also experience something called delirium, which is a more sudden and profound change in their mental functioning. This is a reversible change, however those who experience delirium are also at increased risk for some of these more long-term, subtle cognitive problems.

(15:20):  Finally, graft-versus-host disease (GVHD) is another risk factor for cognitive problems. As you can see, there are multiple unique risk factors that can contribute to experiencing cognitive impairment within this patient group.

(15:35): I want to share some findings from a small study that I published a few years ago. In this study, I evaluated patients as they were first admitted to the hospital for a transplant, prior to them receiving it.  I used a brief cognitive screening test called the Montreal Cognitive Assessment, and surprisingly, I found that even prior to transplant, over 50% of people had what would qualify as at least mild cognitive impairment. However, only 5 of the 65 patients in this study scored in the moderate cognitive impairment range. These findings align with some of what we've already discussed; experiencing cognitive problems are quite common, but usually they are scored within the range of mild cognitive impairment.

(16:45): Within this study, I was able to identify some factors that seemed to increase the risk for patients to experience at least mild cognitive impairment. These findings included people who were older, male, had fewer years of education, had experienced delirium at some time in the past, and some who had experienced different neurological impacts in the past, like a stroke. The risk factors that had the strongest effects included a history of multiple medical problems, and those who had a history of alcohol or substance abuse.

(17:32): Now, let's discuss what we see over time after transplant. This is a larger study from the University of Washington. The different plots you see here are just different tests of cognition, but you can see a pretty consistent pattern regardless of what test is being assessed. Immediately after transplant, there’s an initial dip, or worsening of cognitive function. Then, pretty quickly, you see a rebound or improvement back to where they initially started. 

(18:12): With time, in multiple areas of cognition, you actually see an improvement in cognitive functioning overall, relative to where people started at the time of transplant.

(18:25): I saw something quite similar in my study. On the left of this graph, you can see a dip from their pre-transplant baseline to a month later, which was shortly after the end of their transplant hospitalization. As they were followed for another six months or so, you can see an improvement in cognition. On average, that improvement got them back to a similar place – or actually even a better place – than they were pre-transplant.

(19:03): And then you see a similar but slightly different story when you look at the proportion of people who were impaired.  This is on the right. You might remember I mentioned when patients first came into the hospital before transplant, just over half met the criteria for at least mild impairment. And that number, that proportion of people who were impaired, got steadily better over time. Six months after transplant, the number went from 51% to 36% of people still meeting criteria for cognitive impairment.

(19:43): I then looked at what factors seemed to predict better cognitive outcomes with time -- people who were more likely to improve during the six-month period that we monitored them for.

(20:01): Surprisingly, people with aggressive cancers or aggressive prior treatments showed greater improvement over time. It’s totally the opposite of what you would think.  But I think the key here is what I initially referred to when talking about transplant. For these patients, the transplant is not the first thing that they encounter that's potentially harmful to their cognition. Basically, this group of people who had more aggressive cancers or treatments just had more room to improve based on the prior exposures that they had.  By comparison, if we look at more recent or proximal factors, we see what we would expect, which is that during the actual hospitalization for transplant, those who had less aggressive chemotherapies had more improvement over time.

(21:22): Now let’s look at what other research and literature indicates as factors that seem to be most closely associated with – or most predictive of – people who are going to have more difficulties after transplant.

(21:41): Age is the most consistent predictor of cognitive difficulties, in that older age is a risk factor for worse cognitive outcomes after transplant. However, there are a variety of other important factors as well. For example, people who do not have a spouse or someone living with them in the home don't seem to do as well in terms of their cognitive function over time. People who are obese, or who are taking multiple medications that can affect the brain are also at risk for worse cognitive function over time. And then, as it relates to more cancer-specific factors, allogeneic stem cell transplant recipients as opposed to people who received autologous transplants seem to have worse outcomes. Those who experience severe and chronic graft-versus-host disease (GVHD) also have worse outcomes.

(22:41):  Now, I want to talk a little bit about CAR T-cell therapy. And I'll start by saying there's still a lot we don't know about the relationship between CAR-T and cognitive outcomes. It’s my hope that in the next few years we'll understand it much better.

(23:03): I want to highlight cytokine release syndrome, a possible complication that can arise after receiving CAR T-cell therapy. You probably know about this or have heard about this in other talks, but basically this can occur when the CAR T-cells recognize cancer cells and release very high levels of inflammatory molecules.

(23:30): You can see changes throughout the body that include fever, changes in blood pressure, and in oxygenation.  But specifically in the brain, these high levels of inflammatory molecules can cause a sudden change in mental status. This is called ICANS, or immune effector cell-associated neurotoxicity syndrome. 

(23:49): While ICANS and delirium are not the primary focus in this talk, there is something that I find interesting. In the same way people think inflammation is a primary biological mechanism that causes cognitive problems during cancer treatment in general, inflammation is also the driver here in ICANS. So, when you think about potential risk factors of CAR-T that may cause long-term cognitive problems, it seems like inflammation could be a shared underlying mechanism here.

(24:30): Currently, there have only been a handful of smaller studies that have looked at CAR-T treatment’s impact on the recipient’s cognition. But, like we’ve seen with other aspects of cancer treatment, patients generally have lower than expected cognition at the time of admission for CAR-T and experience a decline at the time of discharge. Then, after being followed for a period of time – like six months or more – overall they don't end with worse cognition than where they started. As always, you might see some variability with this.

(25:23):  As we’ve seen with other cancer treatments, it seems like up to a third of people will still have lower than expected cognition for years after CAR-T. And, as there are multiple aspects of cognition, some may be more impacted than others. 

(25:45): Here is a figure from a study that was published earlier this year. It looked at 106 patients who had received CAR-T, with a little more than half having lymphoma. To clarify, most people didn’t have standard cognitive testing done, and while some completed different tests, many only reported their cognitive function, or their perceived cognition. Again, there's a lot more research needed in this area.

(26:37): In this study, you can see across various aspects of cognition, no more than 20% of patients experienced a decline from pre-CAR-T treatment to six months post CAR-T therapy. And, within the 20%, the areas that were most impacted were the patients' own perceptions of their cognitive difficulties. In this group of patients, 19% showed a substantial decline in their delayed memory over this period, and 15% showed a decline in executive function. Executive function is the strategy or approach with which you might attack a more complicated task.

(27:34): Bringing our focus back to inflammation, which is sort of the most well-studied or understood biological driver of these cognitive changes, it's really interesting to connect some dots here. Inflammation itself increases the risk for cancer, and it also increases risk for cognitive disorders like Alzheimer's disease. We know that levels of inflammatory markers are higher even before cancer treatment, and in those recently diagnosed compared to people without cancer. And in general, again, across a wide range of research, those levels of inflammation go up with chemotherapy, transplant, and during CAR-T. Those inflammatory levels do decline with time after treatment, but even years later, they remain higher than expected for someone who didn't receive treatment.

(28:45): Through multiple studies, it is clear to see that the higher the degree of inflammation experienced, the more cognitive function will be impaired. 

(29:03):  A broader concept I wanted to highlight is that inflammation is one specific biological mechanism. But another theory that's gaining a lot of traction is that cancer and cancer treatment accelerate the aging process. We all know that with older age, our cognitive abilities slowly decline. 

(29:33): One theory is that cancer and cancer treatment accelerate the aging process throughout the body, and the decline in cognition is just how that acceleration is manifesting in the brain.

(29:46): There are a lot of factors that can impair cognition, and if they're addressed, cognition can be substantially improved. These include sleep, mental health symptoms, pain and pain medications, fatigue and abnormalities in blood counts and vitamin levels. When thinking about ways to treat cognitive function, it's important that these are also addressed.

(30:39): Now, there are a few factors during your cancer and cancer treatment that can’t be modified, like how old you are and how many years of education you have. And yes, cancer treatment itself can directly and negatively impact cognitive function, but it also can negatively impact cognitive function through a lot of other pathways – like its impact on sleep or fatigue. There are multiple factors where you can intervene to improve how well your brain is working.

(31:27): There are multiple ways we can measure cognitive function during these studies.  A wide range of clinicians can do things like have you complete a survey to get a sense describing how you feel your cognitive function is. And they can also administer brief screening tests like the Montreal Cognitive Assessment that I mentioned using in my study. That can give a pretty good sense of how things are going.

(31:55): You can also be referred to see a neuropsychologist who would complete a much more in-depth evaluation that could give you detailed information – not just about whether or not your cognitive difficulties are in a problematic or concerning range – but also some nuanced information about the areas of cognition in which you're stronger versus weaker.

(32:21):  One of the survey measures I like is called the PROMIS Cognitive Function. It asks people to rate how often they notice difficulties in eight different aspects of cognition ranging from normal, mild, moderate or severe. Not only does it provide information about our patients’ cognitive difficulties, but I like that it gives a lot more language for us to use in our visit together discussing their experience.  I think there is a lack of language that people are familiar with to describe their problems.  This can help give it a lot more dimensionality. Finally, this next slide gives you a glimpse of the Montreal Cognitive Assessment (MOCA).

(33:18): And now, I want to pivot to talking about treatments. In terms of broad categories, treatments include cognitive rehabilitation, mind-body interventions, physical activity or exercise, and medications.

(33:36):  There are two main categories of cognitive rehabilitation. The first is called Strategy Training and is something that a patient would work on with a speech or occupational therapist, in-person, once a week. The goal of this kind of treatment is to improve awareness of where people are having difficulties, and then problem-solving how to compensate for those difficulties. Many times, this involves figuring out the best way to utilize things like planners, alerts, and sticky notes.

(34:19): The second type of cognitive rehabilitation is called Cognitive Training. It can also be referred to as Brain Training or Brain Games. This usually involves working alone on a computer and doing challenging cognitive tasks in thirty-minute bursts. There are three commercially available programs--HappyNeuron, Luminosity and BrainHQ, which have at least been studied somewhat in the cancer and cognition space.

(34:53): We know that exercise or physical activity is helpful for a wide range of symptoms in cancer, and there's increasing research to suggest that it can be quite helpful for cognition as well.

(35:07): In terms of mind-body interventions, some studies are showing that mindfulness and acupuncture may be beneficial.  The nice thing about mindfulness is that there are multiple different ways in which patients can engage with it. There's a widely renowned program out of UCLA that anyone can sign up for. Your local university might offer mindfulness programs through their integrative medicine departments and there are also a wide range of commercially available apps.

(36:09): When considering using medication, there are two main classes of medications that are used. The first is the stimulant class of medications that are FDA- approved for ADHD. The second class of medications are FDA- approved for Alzheimer's disease. These medications continue to be studied for their effectiveness in cancer patients, and though none of them appear overwhelming in their benefit, they can help.

(36:13): Finally, I highly recommend people adding things into their everyday lives that can be quite beneficial. One strategy is sticking to a regular routine. Another is being thoughtful about when they feel like their brain is working best, and trying to be strategic with utilizing those times to do the most cognitively demanding work.

(36:48): I mentioned strategy training with an occupational therapist, but this is something that a lot of us employ already. 

(37:02): Also, for those who are working or wanting to get back to work, they should be sure to utilize workplace accommodations. Don’t shy away from exploring these options as small modifications within your work environment or work schedule can be advantageous to both you and your employer. 

(37:36):  I'm going to skip how I might approach evaluation and treatment, but there might be time for this in the Q&A.

(37:44):  Finally, I’d highly recommend the book, Improving Cognitive Function after Cancer, by Shelli Kesler, PhD. If people are interested in learning more about this topic, it is written for patients and covers much of what we've discussed today.

(37:59): Conclusion. To summarize, cognitive difficulties are common before, during, and after transplant and CAR-T. But the cognitive problems that patients experience are not specific to these treatments, and depend on the frequency that these problems arose before treatment, and the amount of recovery over time. There are many medications, non-pharmaceutical interventions, and lifestyle strategies that can be helpful and these should all be considered to optimize cognitive function. Thank you.

Question and Answer Session 

(38:45) [Michala O’Brien]: Thank you, Dr. Nakamura, for this excellent presentation. Now let's take some questions.

(39:00): Are creative writing or art activities impacted by chemotherapy or transplant as well?

(39:13) [Dr. Zev Nakamura]: That's a very interesting question. I will say I think it’s been very variable, but from my experience working with patients, I have certain patients who say that they really have difficulties in their everyday tasks, but still feel like they are able to excel in areas like creative writing and art. The other thing is a treatment I didn't talk about that is generally recommended is writing or journaling, because getting practice with trying to communicate concepts in a wide variety of ways does seem to help with brain recovery.

(40:15) [Michala O’Brien]: What kind of skills are tested in the cognitive tests you mentioned?  Are they math, reading, reasoning, or just memory testing?

(40:30) [Dr. Zev Nakamura]: That's a good question. The MOCA test that I mentioned is a cognitive screening test, which means it's very brief and not very in-depth. But each item on the MOCA reflects a much longer version of a test that you might do with a neuropsychologist, therefore it gives you a sample of the range of things that are tested.

(41:11):  In the top left here, they show circles with numbers and letters in them, and the dotted lines show the start of a pattern. The person taking the test is asked to recognize what the pattern is, and to then complete that pattern. During a more in-depth neuropsychology test, not only would that be tested, but also the speed at which people completed it.

(41:37): Other things that are common in neuropsychology testing are things like being able to remember a long list of words, or being able to recite numbers forwards and backwards. Language can also be tested, for example, by giving the person a category – like animals – and then asking them to name as many animals as they can in a minute. Or they're given a letter of the alphabet, and asked to say as many words that they can think of in a minute that start with the letter ‘F’, or something like that. And for each of these tests, it's well established what the normal range is for someone's age, education, and background, and what might be more concerning.

(42:35) [Michala O’Brien]: What do you test for inflammatory markers? Is there a blood test?

(42:42) [Dr. Zev Nakamura]: Great question. There are many clinically available tests that you can get at any doctor's office. C-reactive protein is the most common in terms of ones that are both available and meaningful to interpret. But there are a lot of other inflammatory markers that are primarily reserved for the research setting.

(43:22) [Michala O’Brien]: The annual Medicare wellness visit includes a cognitive and depression screening. Can you elaborate on these?

(43:36) [Dr. Zev Nakamura]: I have never participated in one of these visits, and I'd be interested in hearing more about the question. My guess is that the cognitive screen would involve the Montreal Cognitive Assessment (MOCA) or one of the similar tests like it, like the Mini-Mental Status Exam or there's one called the SLUMS (Saint Louis University Mental Status Exam). The depression screen is usually a sort of survey where you’re asked a few questions to get a sense of whether or not you're experiencing symptoms of depression.

(44:17) [Michala O’Brien]: Is there any research that shows an increased risk of getting Alzheimer's disease after a stem cell transplant, bone marrow transplant, or CAR T-cell therapy?

(44:26) [Dr. Zev Nakamura]: That's a great question, and one in which there is a ton of interest. What I can tell you is that there is either no relationship, or if anything – and we don't understand why this is – there's actually an opposite relationship, where people who are more likely to experience cognitive difficulties with cancer are actually less likely to go on to develop Alzheimer's disease.

(45:06): One thing I experienced a lot clinically is people who go through cancer treatment recognize that there are a lot of symptoms that they might experience afterwards, including potential cognitive difficulties. But I think a lot of times people will come to a clinic with that specific question of, "Do I have early Alzheimer's?" or "Am I going to develop Early Alzheimer's?"  I think that's a really common and major concern for a lot of people. And for the vast majority of people, that's not what's going on when they're noticing difficulties with their memory.

(45:52) [Michala O’Brien]:  Do cancer patients who self-report a positive attitude towards life do better in terms of avoiding aspects of cognitive decline?

(46:05) [Dr. Zev Nakamura]: That's another very interesting question. There is some research about those personality factors, but not very much. There is a lot of research about relationships between things like anxiety or depression symptoms and risk for cognitive problems. And what I can share about that is people who are struggling with symptoms of depression and anxiety are much more likely to also report problems with cognition and be at risk for reporting problems with cognition in the future. There does seem to also be a relationship between things like depression, anxiety and worse cognitive performance on cognitive tests, but that relationship is much weaker than people’s own perceptions of their cognitive difficulties.

(47:05) [Michala O’Brien]: What is happening with memory when you can recall a specific topic that was discussed, but can't recall the details of the conversation. The example is that they know they need to get groceries, but they can't remember what groceries were discussed at home once they're at the grocery store.

(47:30) [Dr. Zev Nakamura]: I think that grocery store example is a common experience that people have. Clinicians who work in the cognition world call this ‘working memory’, which is a little bit different from other aspects of memory. This means that when you make a plan to go to the grocery store and get some things there, you're not truly committing those things to memory. You're just sort of holding them temporarily in the front of your mind or in the front of your brain. And that's what working memory is – your ability to hold those things just long enough until you can get rid of it. It's a similar thing if someone tells you a phone number, and whether you are able to remember and dial that number. That seems to be the aspect of cognition that is most impacted by cancer and cancer treatment.

(48:33): In terms of the other half of the question, about what's going on in the brain to cause that, that's something that we don't understand as well.

(48:49) [Michala O’Brien]: Can cognitive decline get better over time and then decline again? Can there be like a rollercoaster up and down with cognition?

(49:01) [Dr. Zev Nakamura]: Yes, I think that reflects the sort of multiple contributors to cognition. I think in a vacuum, the effects of cancer and cancer treatment should improve over time, but you have a number of other competing factors, and I think the biggest one is aging. If you are 60 when you receive a stem cell transplant, you might experience a dip in cognition that improves over time. But in the background, there's also the effects of aging on your cognitive function. Someone in that scenario might experience what feels like an improvement, followed by a decline. And then, as I mentioned, many other things could contribute to more of an up-and-down effect, like what's going on with sleep or what's going on with mood and those sorts of things.

(49:57) [Michala O’Brien]: Are there any differences in cognitive decline in somebody under 40? This person has noticed issues with memory and executive function decline, and it was very difficult after chemo. Is that normal? And when would this cognitive decline potentially improve?

(50:19) [Dr. Zev Nakamura]: I would say that for simplicity in this talk, I emphasized that older age is a risk factor for cognitive decline, and that's definitely true of tested cognitive difficulties.

(50:42): But when we focus on the patient-reported cognitive function, we almost see the opposite, which is that younger folks are more likely to notice a decline in their cognition. And I think there are several reasons for that. I think younger people are generally starting in a better place. They are more likely to be doing things day to day that are more cognitively demanding of them. They're more likely to notice. And then at the extremes, people who actually have substantial impairment in their cognitive function are super aware of it.

(51:24): In terms of what to do about this or think about it improving, I had to unfortunately skip my clinical approach to this. But I think because there are so many factors, the thing that I've seen work the best for patients is taking a multipronged approach. For the cognitive problems specifically, get connected with a speech therapist to work on cognitive rehabilitation. I actually can't think of a patient whom I referred to cognitive rehabilitation who didn't feel like it was helpful.

(52:00): And then for a subset of patients, potentially trying things like a stimulant medication, or the medications that are used for Alzheimer's. But much more importantly, also looking at all those other factors. Is there a nutritional deficiency that can be tested? Is there mental health or fatigue or a sleep issue that can be optimized?  When I'm working with patients, I'm usually trying to do many of those things all at once.

(52:42) [Michala O’Brien]: Are there any sleeping medications that could interfere with cognitive health after treatment?

(52:50) [Dr. Zev Nakamura]: Yes. Sometimes folks are prescribed medications in the benzodiazepine class for sleep. Some names of those medications are lorazepam (Ativan), alprazolam (Xanax), or clonazepam (Klonopin), and those can be helpful medications for anxiety and for some people, sleep. But those also definitely are known to have adverse cognitive effects. When I'm working with patients who are on those medications, we work to try to transition off of them so that we're minimizing any contributors that could have negative impacts on cognitive health.

(53:35) [Michala O’Brien]: Can you comment about current warnings about diphenhydramine (Benadryl) and its effect on the brain? Is there any other substitutes for allergy sufferers?

(53:48) [Dr. Zev Nakamura]:  I don't think of Benadryl as being as bad as some of those benzodiazepine medications, but I appreciate the audience member bringing that up because antihistamines, like Benadryl or other medications, have what we call ‘anticholinergic properties’ that can have negative effects on cognition. So, Benadryl does, absolutely. For the specific question about treating allergies, there are other medications, like loratadine (Claritin), that work well for allergies and don't cross over into the brain as much. These are much more recommended for people who are trying to simultaneously manage allergies, but minimize medications that could have negative cognitive effects.

(54:52) [Michala O’Brien]: What about trazodone that's been prescribed for sleep? Do you have any comments on that one?

(55:00) [Dr. Zev Nakamura]: I utilize a lot of trazodone. I find that it's helpful and does not have negative effects on cognition. I know some of my colleagues, who are sleep specialists, don’t think that trazodone is actually that effective of a medication in terms of its benefit for sleep. But I do use it a lot because the patients I have treated do find it helpful. And, it's not a risky medication in terms of negative cognitive effects.

(55:36) [Michala O’Brien]: Does induction therapy for multiple myeloma qualify as chemotherapy?

(55:44) [Dr. Zev Nakamura]: It does, and many times the induction therapies are high-intensity therapies that require a hospital admission to receive, as opposed to something that folks would get in the outpatient setting. Those higher-intensity regimens that require hospitalizations do seem to be more closely associated with negative cognitive effects than other aspects of cancer treatment.

(56:21) [Michala O’Brien]: You mentioned a couple of apps in the presentation to help with cognitive issues. Is there one that's specific for reading? This person has noticed their reading has become more difficult.

(56:36) [Dr. Zev Nakamura]: Oh, that's interesting. None of the apps that I highlighted are particularly focused on reading. For this audience member, I actually think it could be helpful for them to consider getting a referral to neuropsychology because there are so many different things that could be impacting their ability to read. A better understanding of what aspect of their cognition is being affected will be helpful for this person to know what kind of treatment might be most helpful.

(57:16) [Michala O’Brien]: This will have to be our last question. Have graft-versus-host disease (GVHD) medications been found to prolong cognitive or memory issues? And then the second follow-up is-- when they're stopped, is there a similar improvement?

(57:35) [Dr. Zev Nakamura]: I think this person is probably referring to immunosuppressive agents. And if that's the case, I think that the relationship is not particularly well understood. There is some research to suggest that they may worsen cognitive function, or at least in some subgroups of people. I'm not aware of any research about what happens once they're stopped.

(58:09) [Michala O’Brien]: Closing. On behalf of BMT InfoNet and our partners, thank you, Dr. Nakamura, for a very helpful and informative presentation. And thank you to the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way