Dinender K. Singla, PhD, professor & head of the division of cardiovascular sciences at the University of Central Florida College of Medicine, talks about chemotherapy causing brain fog.
So, to start off, if you could just briefly explain your study, what it’s about and how it works.
SINGLA: So recently we would like to investigate how anti-cancer drugs causes toxicity. So I have around 25 years of experience working in the heart. And recently in the last two, three years, we investigate how those drugs cause muscle fatigue, muscle toxicity. And in the grant supplement, which NIH would like to understand, it is a drug causes any other additional affect, especially in the aging population or in the neurotoxicity. This is a unique grant. We would like to investigate whether these anticancer drugs can cause neurotoxicity. The most important point is like most of these anticancer drugs they do not pass a generic blood brain barrier, which we haven’t. And the question is why these patients are still getting cognitive dysfunction, dementia, or they feel their tiredness in the brain.
And how are you testing this in your study?
SINGLA: So to establish this, we took mice. We have not done any human research yet. But we have the mice. We injected the doxorubicin into them, and then we took the brain out and see, is there any pathological changes which are happening in the humans that can correlate in these animals? First we did the functional test, which is called a rotarod test and a maze test that tests function of brains were decreased. It means, yes, doxorubicin is affecting the brain function. From brain function, we would like to see the pathology. Then we see when doxorubicin is not passing through the blood brain barrier, what could be the other thing? That we find the signs of inflammation. Inflammation-wise in those brain cells, and it means that inflammation is playing a role. Another novel aspect of this study is people believe nothing can pass from blood brain barrier easily. But we are investigating there are monocytes which are present in the vasculature – of brain vasculature can pass through the blood brain barrier. Only then maybe one study to that, maybe nothing. But in the case of doxorubicin toxicity, which concept we are planning to establish is brand new. Nobody has even a single paper under that giving doxorubicin can infiltrate monocytes, which are inflammatory cells in the brain. Then we are linking that inflammation to a novel form of cell that called (unintelligible) process. So which inflammation is there because of monocyte, it causes the further cell death in the neurons in the other many different types of brain cells. We are still kind of – we say new and they are not published yet. And then for the layperson, could you break down what is doxorubicin and what’s the treatment look like for a patient?
Doxorubicin is a novel drug, OK? You just name it. You can say the ’70s, this drug started being used and given more rapidly to save the patients, especially to the breast cancer patients. Now, there are lots of drugs available in the market. And doxorubicin still acts as a beautiful drug, which we need to given the patient? It depends on the patient situation, how severe cancer you have it. You have one type of cancer, more types of cancer in the same patient and how widely it is spread. So, in the recent literature, there are also some inflammation drugs to treat the cancers. Even still, in many cases, you need doxorubicin, which is a kind of a unique drug available to the cancer patients.
Yeah, I wanted to ask, if it’s causing these adverse effects, why use it?
SINGLA: Because this is a beautiful drug. This can act onto a majority of the dividing cells, as, of course, any – there are always a side effect. That is where now we are getting into OK, if we can treat the mechanism, the way it kills cancer cells are different, OK, compared with the other body cells. But we – our colleague, which we have a co-grant. We are showing exosomes reduce the tumor, reduce the tumor further and will protect the muscle. But we have not tested that in the brain yet. But we are – but we have proposed those studies in the brain, yes.
And what are the other side effects? You mentioned cardiotoxicity, muscle toxicity …
SINGLA: The side effect of doxorubicin basically falls in two different categories. One is the acute side effect. Another are the chronic side effect. Acute side effects, sometimes is the hair loss or some people get arrhythmia, tachycardia. So many of the cases, those side effects can be repaired within one month, two months, six months. Like sometimes patients treated with doxorubicin get a headache, (unintelligible). And those can be treated. In other patients are not getting treated. Now, your question will be why other patients are not getting treated and they develop a chronic toxicity? It goes through many different directions, OK? And some of the directions are how old the patient is, what kind of socioeconomic environment the person is living? What kind of a social gathering he lives in? How much stress he gets? Are they having certain genes which are prone and (unintelligible) regulated during your drug treatment? And they are not showing the effect immediately, but they can show that effect after one month, six months, six years or ten years. And because there are certain patients of doxorubicin treated, we see the development of cardiomyopathy even after 20 years. So this is kind of now becoming more and more urgent to investigate these effects. How long? Because we are going to have a very beautiful young cancer survivors. So if they are going to develop this kind of side effect, even a cognitive dysfunction after 10 years, after 15 years, are they going to live their whole life like that? Are they going to develop Alzheimer’s disease in the young age, which we consider so far is the oldest disease? So those – first to make sure we are healthy. We are living in a good society. And these cancer survivors can have a quality of life. We need to look into that in more detail.
And is these cognitive decline a side effect only of doxorubicin or is it of any cancer treatment?
SINGLA: I would not say any cancer drugs. But there are now more and more literature coming, yes. Many of the anti-cancer drugs are causing those cognitive dysfunctions.
And then what was the rate have you noticed the correlation between this treatment and development of Alzheimer’s or dementia?
SINGLA: So see, development of dementia and Alzheimer’s sometime it comes in the later stages, OK? And we have investigated, at least in our research in the animals, there are certain markers – OK? – like base one and some other neurological markers, they are up regulated in these patients. Now, the question is, what – if you keep these (unintelligible) long term, what if they go back? As I said, some of the effects are reversible or they are permanent. We do not know that yet. So those will be – we will be investigating. If we are doing a long term study, we will understand are really these are permanent? Or they can, like, some time what happens is when you give the drug, immediately it show – start showing you the signs of many diseases. But your body itself is so strong, immune system, it suppresses because the drug is given at a certain time. Then the question becomes how the drug is given? How long the drug is given? So all those factors needs to be keeping in mind when you think about how this neurotoxicity or cardiotoxicity or muscle toxicity is caused by these drugs.
And you’re talking about how it can take a long time for these to develop?
SINGLA: That is correct.
Does it gradually onset? Will you notice it at a certain point?
SINGLA: See, there are well-published studies, OK? And certain people having a powerful gene – OK? – which if they’re getting that doxorubicin or anti-cancer treatment, they can definitely develop a significant cognitive dysfunction. Then it is another concern. They are also developing a cognitive dysfunction. We are doing the studies after we know these cancer patients do have it. There are published studies out there. It was recognized many years back. Now it is becoming more and more to know it really is happening. Because earlier what happens was that cancer was considered as a kind of terminal disease. People get a cancer, they die. We do not know much about it. And people keep living whatever they have it. We just ignore the patients. In other persons of the cancer, he got a treatment. That’s why he has some problems. But now I think we are going to make people live longer. Cancer is not a terminal disease anymore. It will be a manageable disease which can be prevented. And I am very hopeful another 20 years, cancer will – nobody will consider cancer as a big deal, which we are thinking. Thirty years back we are not thinking this. Now we say you got cancer, we still get scared. We get stressed, OK? But we say when we are learning, oh, 10 of the people got cured out of 20 or 15 even. Our – we are getting increased. Like today you’re feeling much better when you know COVID-19 vaccine has come. So this is the feeling we are developing. If you are having that survival society that we want that survival society should be healthy with a beautiful quality of life they can live. We do not want them – they are living cured from cancer and now having neurotoxicity or Alzheimer’s disease or some other dementia. We don’t want that. So it’s better – we pay attention allow.
And then again, for the layperson, when you’re talking about neurotoxicity and brain fog, what does brain fog look like? How does this neurotoxicity present?
SINGLA: So, see, brain fog is kind of a decline in function. Like when somebody gets the cancer drugs, doxorubicin or other kinds of drugs, you start feeling tiredness. You start feeling signs of memory loss. So, like your brain is kind of foggy. You cannot see the thing with that clarity, with many different ways. You cannot, like, to perform your work that well as you were doing before, OK? So those things will consider a combination of many things. It is a general term, like a layman tell me, say, oh, my brain is like foggy and I’m feeling not – clarity is not there. So that’s called a chemo brain or chemo fog, or a brain is foggy with cancer patients. That’s how we define it.
And then could you walk me through that moment in your research where you discovered that the cell death was correlated to the treatment?
SINGLA: Like we are now, first, we want to identify in those animals where we are giving doxorubicin are having signs of decline, cognitive function, cell death – of inflammatory cell death and the development of some neurofibrillary tangles or some other (unintelligible) antibodies. But those are the signs of all brain – we call it as a brain remodeling. Remodeling means whatever the brain was in the presetting now it is having new settings with abnormal changes, OK? And we do observe brain size also decreases – OK? – in those treatments. And now we are having an embryonic stem cell-derived exosomes. Exosomes are very, very small components which are secreted by the all body cells. Now, I will not go into detail of exosomes, but I only tell you that exosomes can be bad, can be good. It depends where you’re taking from. But exosomes we are taking from the embryonic stem cells, which are healthy, which we are using to regenerate the body. It simply means is it contains many component which are going to decrease the brain fog, cell death and improve the brain function. That is where we are heading towards. If it is true that we may look into what is a specific component, which is improving the brain function and cell death, or we do need the whole exosomes, which is a – which can easily be translated into the clinic. Because these are very small molecules, they are secreted in the media by the embryonic stem cells. You do not need the stem cells which we have a fear they may cause a tumor. The stress of that is not there. They contains proteins. They contain anti-inflammatory cytokines. So that’s where we are trying to treat this one.
I was reading in your article you called it a tangling of neurons can you illustrate what that means for us?
SINGLA: So tangling of the neurons is the release of a myelin protein. And when the cells are dying, or the cells are changing the shape and then there’s a new neurofibril tangle is formed. So that’s a kind of a pathological sign of brain remodeling.
And then I know we talked about this a little bit before. If you don’t mind discussing maybe when you saw your grandfather and they were like, no, no, don’t talk about it, don’t talk about cancer?
SINGLA: OK. See, let me tell you. I really do not know for sure because I was in grade 10, OK? And grade 11 and when I talk to my grandma and that cancer was just coming there in the early ’80s, there were less cases. And whenever I talked to her, she said, no, don’t talk about it! In my own language. She was scared of listening to the word cancer because the belief was anybody get cancer, you will die of it, OK? And I didn’t know what cancer is. And so then slowly, slowly, I learned my grandfather, when I was born around six months old or something in the ’60s, he died because of a brain tumor. But they are not definite about it because at that time there was no treatment kind of in India. I’m born and brought up in India.
And what do you hope to do with the results of this research? How do you hope to help people who are experiencing cognitive decline?
SINGLA: First, if we understand the pathophysiology, we understand we have that treatment, it definitely will benefit, especially to the people who are developing, young people, and then will improve the quality of life. And they will decrease the hospitalization burden in the future. Because if you are treated for the cancer and you’re not dying because of some disease or dementia as well as wherever you go and talk you are having the same level of confidence if you are treated properly as anybody, non-cancer individuals. It will definitely improve a quality of life. That is our ultimate goal.
Can you speak to a little bit about maybe some of those other side effects we talked about, like age or if you’re a single mom and those kinds of things?
SINGLA: So another question comes, OK? Some people say, oh, I am a cancer survivor. I’m healthy. I have no problem. And others say, no, I’m having some – little bit of a brain fog. I’m not that much healthy. Now the question comes, what is going on? Why these two people are different? There could be multiple reasons. One, it could be age factor, and another is it could be a socioeconomic factor. What kind of fear or how much stress do you have other than the cancer? Do you have any bills to pay? Are you a single mom or you are nobody takes care of it or somebody says, don’t worry about it, we’ll take care of your cancer. Whole family goes with you to get you treated for the cancer. Your morale changes completely. When the patient comes, he’s talking of stressed things. And then the other person says, don’t worry about it. Your environment is healthy. That person may not develop the dementia, may not develop or this can be delayed, OK? It depends. If your genetic system is like that, you know, there are certain evidence that genes are responsible, which alters during doxorubicin treatment, or they can come up again and cause you dementia or those things. And all these things play a huge role. On the top of it, let me go further here. Somebody has some diabetes. Somebody has some heart disease. At the same time, the person got a cancer. Now you’re not treating with the cancer drugs only. There are multiple drugs you have to give to the person to control the cancer. That could be another reason causing you a dementia. So, on the contrary of that, a person is completely healthy. He has a healthy environment. And he got cancer. He’s getting a treatment. He doesn’t care about anything. So, the chances of getting dementia, Alzheimer’s disease or cognitive dysfunction are much lower over there. So, all of these depend because we are not working for only one class of people. Our goal is to see even if one patient is suffering, if we can reach to that patient. We make sure when you are treating the patient, are you asking those questions? Are you just ignoring them when the patient says, I’m having this problem that probably said, oh, don’t worry about this happening because of your treatment. So do we involve more psychologists? Is this a real thing? How far this can go? But many of the time, you know that it’s general human nature. If somebody is sick at home, we say, well, the person is complaining. Well, the person is sick. Some people pay more attention. So with all those drugs that do cause significant effect. So my research will go there and tell them these things are real. These things are happening. We will be reshaping our discussion with the patient. We are not here to just ignore them. It happened because of your tumor. It is happening. Their tumor is getting cured because of these anticancer drugs. That’s a massive – we’re trying to ultimately get it out there.
And have you noticed at this point if it’s a result of longer term for the treatment or if it can happen at any exposure to the treatment?
SINGLA: It depends how the drug is given. Because let’s say you are asking now why this drug doxorubicin is in the market, OK? In the beginning, the drug was given high dose for four days in a row through I.V. injections. Then the people and doctors learned drug has to be given in a low dose. Then you have lower dose has a limit also. You cannot give a low dose, it could not cure the cancer. So, this is the puzzle around here. So now all those other good questions, which I do not know, but we have learned based on research, clinical research, not animal research, and there are a significant number of patients. They are developing one or another type of symptoms. It could be a decrease in thinking, stressing, staying all over thinking what is happening, what will happen to me? It could be long term that the fear of recurrence of the disease and could be attention deficiency. Some people think, oh, I can retire now. I cannot function properly. Now, many of the time those people are getting ignored. You do not want young people are getting cancer treatment, becoming a cancer survivor. Do you really want them to retire at 25 or 30 years of age? So those will be the burning concerns. That is where we are going to think about it in the future.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
SUHTLING WONG-VIENNEAU
Sign up for a free weekly e-mail on Medical Breakthroughs called First to Know by clicking here
