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One in every six people around the world live with a neurological disorder — a broad term used to describe things such as Alzheimer's disease, epilepsy, multiple sclerosis, or headaches. The first-of-its-kind Cleveland Clinic Brain Study is aiming to identify biomarkers of these disorders, so doctors can hopefully better predict who might develop a neurological disorder, potentially transforming the future of healthcare. Dr. Imad Najm, the study’s co-PI, discusses how the study came about, what makes the study so groundbreaking, and what other goals doctors hope to achieve.

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Cleveland Clinic Brain Study with Dr. Imad Najm

Podcast Transcript

Annie Zaleski: Hello, and thank you for joining us for this episode of the Health Essentials Podcast. I'm your host, Annie Zaleski, and today we're talking about the groundbreaking Cleveland Clinic Brain Study with the study's co-PI, Dr. Imad Najm, Director of Cleveland Clinic's Epilepsy Center at the Cleveland Clinic Neurological Institute.

Annie Zaleski: One in every six people around the world live with a neurological disorder, a broad term used to describe things such as Alzheimer's disease, epilepsy, multiple sclerosis, headaches or a stroke. Although you can make lifestyle changes to decrease your risk of developing any of these conditions, doctors still can't pinpoint exactly why some people develop them and others don't. However, the first of its kind, Cleveland Clinic Brain Study, is aiming to identify biomarkers of these disorders, so doctors can prevent certain neurological disorders from happening and maybe even stop or slow the progression of these diseases after diagnosis. Dr. Najm is here to discuss how the study came about, what makes the study so groundbreaking, and what other goals doctors hope to achieve. Dr. Najm, thank you so much for being here today.

Dr. Imad Najm: I'm glad to be here.

Annie Zaleski: So I'd like to start off by having you tell us a little bit about your work here at the Cleveland Clinic. What kind of research and clinical work do you do in addition to your involvement in the brain study?

Dr. Imad Najm: Yes, I am a neurologist by training with subspecialty training in epilepsy. So my daily clinical work is in the Epilepsy Center at the Neurological Institute. I take care of patients with epilepsy, but mainly I deal with patients with complex epilepsy problems. My research over the years have been focused on the better understanding of why epilepsy happened in some patients who have what we call malformations in the brain and, in particular, I mean, just identifying what we call biomarkers of the disease during its progression as epilepsy, difficult to treat with multiple antiseizure medications.

Annie Zaleski: So this brain study is really kind of a natural progression and outgrowth of everything you've already been doing. So this is great.

Dr. Imad Najm: Absolutely. Yeah, I mean the brain study is ... the idea of it basically started by our experience as clinicians in everyday practice. And it would be an epilepsy, it could be Alzheimer's, it could be stroke, Parkinson’s. And this is where the whole idea came from and our interest and excitement in being part of it.

Annie Zaleski: So those are neurological diseases. And so can you give, I guess, for people who might not be familiar, what is sort of the definition of a neurological disease?

Dr. Imad Najm: Well, the broad definition of neurological disease is any disorder that affects mainly the brain or part of the brain. I mean, some examples of this that we may be familiar with will include a disease such as multiple sclerosis, a disease such as stroke, a disease such as Parkinson's, Alzheimer's, dementias, other movement disorders. So any of these disorders that affect either one part of the brain or the whole brain would qualify for the designation as a neurological disease or neurological disorder.

Annie Zaleski: What makes diagnosing these neurological diseases so challenging?

Dr. Imad Najm: Yes, the current diagnosis of most neurological disorders today is based on clinical, sometimes imaging neurophysiological such as EEG, electroencephalogram, and multiple lab studies that could be helpful only after the disease has progressed in most of these neurological problems. In other words, the diagnosis is made after the damage of the brain has been done. To date, there has been an insurmountable challenge to our quest for the curing of, or reversing the impact of many of, these neurological disorders, but in particular, laws called neurodegenerative diseases.

Annie Zaleski: Well, and as you kind of explain it there, I would think the advantage of identifying and diagnosing these diseases early — so you stopped that degeneration from happening — so you kind of cut it off at the past, almost.

Dr. Imad Najm: Absolutely, absolutely. I think the biggest challenge is to make the diagnosis before the disease has had time to affect the brain to destroy these neurons and make it almost irreversible progression of the clinical presentation and devastation that ensues from the disease progression.

Annie Zaleski: So in terms of the brain study then, you mentioned that it was definitely rooted in so much of the research that's happened. How long ago did this idea for the study develop, then, that people decided, “Hey, we're going to do this”?

Dr. Imad Najm: Yes, as I mentioned earlier, all of us in clinical practice, we every day face the problem of making a diagnosis and knowing the time we make the diagnosis that there's not much we can do. In particular, we cannot reverse what has happened and we can never cure that disease. So the idea about the Cleveland Clinic Brain Study started maybe five, six years ago, and you are in a meeting between myself and Dr. Machado, who is the Chair of the Neurological Institute at Cleveland Clinic, where we were talking about ideas for the future in how we can — as the Neurological Institute and Cleveland Clinic — we can make a dent in our understanding and in our treatment of patients with neurological disorders. And we started the discussion on what is something that could be done. And then during the discussion, we started to think about what other ways, other specialties that have addressed problems.

Dr. Imad Najm: In particular, we focused on the heart and cardiovascular disorders. And then, we started to analyze why and how we are now in a situation from a cardiology standpoint that we are able to prevent many of the most devastating cardiovascular disorders. And then one study came up very clear to us, which is what is called the Framingham Study. And the Framingham Study — many of us know about it — but this is a study that started in 1947 after the second World War, when people coming back excited and big use, heavy use of fat in diet, for example, and smoking. And nobody would understand the impact of many of the diseases that we suffer from such as high blood pressure, diabetes. And that was big problem with people in their 40s having heart attacks and dying. So the idea here came from the public health service that preceded the National Institute of Health, started a study to understand on a large population, over time, what could be the risk factors that determine the occurrence of cardiovascular diseases.

Dr. Imad Najm: And the Framingham Study, it is one of the most impactful studies in the history of cardiovascular disorders because it enabled us to understand that smoking is bad for heart diseases, that diabetes, high blood pressure that are uncontrolled may lead to a significant increase in the incidence of cardiovascular disorders. This led to the development of medication for blood pressure, better control of diabetes and developing the development of medications, such as statin that led to a significant decrease of coronary artery diseases. So we thought, “Why can't we do something like this for the brain?” But immediately, we understood that it took 30 years or 40 years for a government agency to support a study. How can a small institute like the Neurological Institute, relatively speaking, and the Cleveland Clinic, even though it's so large and powerful, embark into something like this?

Dr. Imad Najm: We knew from the beginning that it is going to be very difficult for us to get off the bat funding from government agencies choices. Because the National Institute of Health would love to help in the process but not in a five-, 10-year process of collecting data with no results. So we decided to model our Cleveland Clinical Brain Study to the Framingham Study, but at the same time, getting the resources and the money from philanthropy and from donations rather than from the NIH in the beginning. The main goal here for us is to understand what are what we call biomarkers of disease development before the disease starts. And that has been a subject of big discussions internally about, OK, what age should we start enrolling people? We cannot start at birth because it's going to take us 70 or 80 years. And that's why we decided to enroll healthy volunteers at an age where we think the silent phase of the disease may be starting in some of us. And that's why we chose 50 years and older.

Annie Zaleski: So what are some of these biomarkers then, that you hope to find? And what are some of the ones that you're already kind of aware of and know about that are signs of neurological disease?

Dr. Imad Najm: Yes, the biomarkers that we are hoping to define are maybe potentially some genetic biomarkers. Some genetics could be at the DNA level, could be at what we call the epigenetics thing, which is the change in DNA in the process called methylation. And this happened, by the way, after birth and it's not affected mostly by heavy detail problems. And then there would be what we call the transcriptomics. It means looking at the RNA, the part of the genome that translates the message from the DNA to produce a protein that will provide the function of a cell or a dysfunction of a particular area of the brain. And then, we're looking at biomarkers in the blood. That would include proteins. For example, something that we talk about in brain disorders now such as neuro inflammation, neuro inflammatory biomarkers, proteins and the blood. And then, we're looking at something in our gut that may give an indication about something that may be affecting the brain. That's why looking at the stool and what we call the microbiome. These are some of the biomarkers from bio samples — from the blood and the stool.

Dr. Imad Najm: In addition, we are looking for biomarkers using state-of-the-art technologies. Using, for example, retina scan. A scan through the eye that takes maybe five minutes or less, giving us an indication what may be going on in the brain. Why the retina? You may ask what does the eye have to do with the brain? So the eye, in particular the retina, it is part of the nervous system and the neurological systems and because the cells in the retina are actually neurons and there is a nerve called the optic nerve going to the brain. So there are some indications. Actually, you asked what are the currently available biomarkers... There's a small indication now that is not proven that looking at the retina, for example, we can see some plaques even before Alzheimer’s disease as a disorder starts to happen.

Dr. Imad Najm: So we hope, using for example OCT, which is a retina scan, to understand, to get some insight into the brain before things happen. Of course, we are using state-of-the-art MRI technologies to scan the brain to use almost every type of sequence or process that we have in our hands to image almost everything we can. Then, in addition to that, we are looking at the relation between the heart and the brain. We're looking at electrocardiogram, just simply looking at the heart rate. Does it give us some prediction of something to happen? And we are looking at the echocardiogram, looking at the pump, because when we do the echocardiogram, or the cardiologist, they do echocardiogram, they look at the pump and say, "Well, it is within normal limits." But what if a person who's 20 years old has an 80% of their pump working to send the volume to the rest of the body? What if it is 75% or 70%, which practically is normal? But does it affect this, what we call maybe less perfusion or less blood going to the brain, although it's deemed to be adequate but may be impacting the brain on the long run?

Dr. Imad Najm: Then in addition to that, we're looking at cognition. We are trying to understand where we are from the intellectual standpoint, from a memory standpoint, and to assess the function of the brain as we age. Another thing that we may be adding in the future could be something like recording simply the voice. We know now there are some changes that may be happening in our tone, the cadence of the words, the content of what we say that may be changing during the early stages of an early degenerative disease, such as Parkinson’s, such as Alzheimer’s, dementia. So these are some of the biomarkers that we think we'll be looking for. Now I can tell you, we will have access to billions and billions of data points per individual and using now the modern science of bioinformatics, artificial intelligence, machine learning — I think we're going to uncover much more than we are thinking about and in particular, we may be discovering things that we never thought about.

Annie Zaleski: That is just all so exciting and I think what's so exciting about it is you're bringing so many different areas together in one thing and that it's very much like it's not just studying the brain — it's everything else that goes into it. That's incredible.

Dr. Imad Najm: We are certainly excited about it. And in addition to that, we are not collecting a set of data at one single time point. We are collecting set of data year after year and following up with our volunteers into later stages of their lives and trying to find out what we are finding or what we are observing with time. And in particular, if at certain point, what we call an inflection point, when they develop the disease, what are the changes you are seeing when the disease now developed clinically? But more importantly, what are the footprints of the disease during that silent period during which the brain has been transformed from a healthy one to a brain with some problem or some pathological changes?

Annie Zaleski: So in light of just how much is being tracked, what departments and specialists are also involved in the study?

Dr. Imad Najm: It is a multidisciplinary effort. We have many institutes and departments within the Cleveland Clinic that have been and will be in the future involved. To give you examples, we have multiple departments or centers within the Neurological Institute. I can name a few. I can name the Center for Brain Health, the Dementia Department, the Center for Behavioral Health, Psychiatry, the Epilepsy Center, the Strokes and Cardiovascular Center, the Center for Multiple Sclerosis, and multiple other centers within the Neurological Institute. Outside the Neurological Institute, we have very strong collaboration and involvement of colleagues from the Heart and Vascular Institute, from Head and Neck Institute, of course from Lerner Research Institute, and the Lab Institute and others.

Annie Zaleski: In the study, then, are people joining over time? Because I understand that this is going to be a 20-year period of tracking. Are people going to jump in maybe 10 years down the line, or how is that kind of going to work? How are you envisioning that?

Dr. Imad Najm: Yes, actually, we are envisioning this as people with time enrolling in the study. Unfortunately, we cannot enroll all 10,000 initial people in the first year. So it is a process that is going to take time and it's going to take a lot of logistical adjustments in order for us to be able to perform all these studies on each one once a year. So far, we've been so heartened by the excitement of the community at large and even people from outside Northeast Ohio. We have people from many states outside Ohio inquiring about the study and how excited they are to participate if they do qualify for the study. So, so far, we have more than 8,300 individuals who signed up for the study. Signing up doesn't mean they qualify for it because we are looking for healthy volunteers.

Dr. Imad Najm: From a brain standpoint, it doesn't matter if somebody has any other disease in the body, as long as they're neurologically healthy, we will take them. But we have to go through screening process and then to schedule the initial appointment, which now we are making some inroads with this. Not as fast as we want, but we are ramping up our recruitment process every day and, we think, starting in beginning of 2023, we'll be able to enroll anywhere between 200 and 250 individuals per month, which will give us around 2,400 to 3,000 per year, which is much more than we thought we'd be doing. Will put us on pace to enroll the first 10,000 individuals somewhere between three and four years after we started the study.

Annie Zaleski: So when you say someone needs to be neurologically healthy, what does that look like, then? What does that mean just in terms of ... so, I guess, what does that mean?

Dr. Imad Najm: It means the person doesn't have a history of stroke, the history of multiple sclerosis, of Alzheimer's, epilepsy or Parkinson's disease. In addition to that, we examine all of the individuals. We do a thorough neurological exam, a thorough neurocognitive exam, MRI and all of the studies. And we can determine based on the technology of 2022 if this person has a neurological disorder or not. And if they have a neurological disorder, we can refer them to the appropriate center, subspecialty center, within the Neurological Institute or anywhere they would like to receive their care.

Annie Zaleski: So with all of the things that are being tracked, then, if someone does make it in the study, what is it going to look like for them, to be tracked? Would they go somewhere for an entire day and have a battery of tests? What is that going to look like?

Dr. Imad Najm: Yes. The way each person, when they decide to be enrolled and they’re deemed to be good candidates for, they will be scheduled for all of these tests or multiple tests over 18-hour period. So a typical schedule would be the person to check in around 4 o'clock in the afternoon, currently at the main campus. And then after that, they will have the eye exam, the eye scan. Then, the MRI of the brain. Then, they will check in the hotel across the street and they will have their dinner. They will go after that to have a sleep study and EEG overnight that will be hooked to the electros for recording of their brain waves. Wake up in the morning, they will be unhooked. They will have their breakfast and go to the testing center for the Cleveland Clinic Brain Study, where a full neurological exam, done by an experienced provider, will be performed.

Dr. Imad Najm: Plus, we have a digital neurological exam as well to give us less subjective and more objective determination of what's going on. Then, they will have a neurocognitive test to look for memory and cognition. And they may have additional tests, now or in the future, like I mentioned, for example, voice recordings. And then, of course, we connect blood samples, and if they do have any stool samples to give us. That will be more or less the typical enrollment exam or tests and this will be done almost every year. Some tests, for example, MRI, we'll do them every other year. The echocardiogram, we'll do it every five years. Other tests like the electrocardiogram, neurological exam, the blood testing, will be done on yearly basis. And in between, we may be in touch with our volunteers with some brief questionnaires to understand how they're doing; if there is anything new that may have happened.

Annie Zaleski: That's all very efficient. And for someone who's looking to be in this, then, that's very easy to compartmentalize. It's not like you have to go every six months and do something different. So that's a really great setup.

Dr. Imad Najm: Yeah, so far we had good feedback from our volunteers. We always ask for suggestions for improvement because we started this study from scratch. We have created a study that requires multiple tests that we are compressing them into 18-hour period. So there are areas of improvement that we always are very happy to hear from our volunteers about suggestions how to make the flow better. But so far, has been very, very good.

Annie Zaleski: So in addition to helping doctors find new ways to prevent a lot of these neurological disorders or identify them before they happen, what about treatment, then? After the study is said and done, looking at results, is it a possibility that doctors are also going to find new ways to treat people after they've been diagnosed, then?

Dr. Imad Najm: That is the most exciting part of the study and the overarching goal of the study, which is not only to diagnose, which we've been doing in neurology for 50, 60, 70, 80 years. We are here to diagnose and treat ... and even I can take it one step further — our dream is to not only diagnose, but to even predict who is going to develop a disease and come up with a treatment to prevent it rather than to deal with the consequence of a disease that has already developed.

Dr. Imad Najm: So the biomarkers that we are looking for, in particular the blood biomarkers, they could be used to make a diagnosis. We can do a blood test, say, "Oh, you are at risk of developing Alzheimer's." But same time, we can see some of these biomarkers may be targets for treatment. And that is, I think, the most exciting part. For example, if we find a particular protein in the blood that is telling us this person is going to develop Parkinson's in five years from now, we can go and partner with companies, governments, institutions all over the world and get together and design a drug, a medication, that can be given to target that particular protein.

Dr. Imad Najm: And doing so, there will be a significant chance of not only treating a particular neurological disorder, but more importantly, to prevent that disorder from happening. And, therefore, we don't need to deal with any disabling consequence of even the start of a neurological problem. That is our dream and this is what we hope we'll be achieving.

Annie Zaleski: I mean, that's just transformative. That could change so many people's lives, in addition to changing medicine.

Dr. Imad Najm: Absolutely. It will change people's lives. It will change how society is allocating resources and how we age into a much happier environment than some of us, unfortunately, have to endure — not only as patients, but as families and as society in general.

Annie Zaleski: So as the study progresses, then, will you be releasing any interesting findings early or is it only going to be kind of at the 20-year mark that things will emerge?

Dr. Imad Najm: No, we will be releasing information as we have it. We don't want to delay things. We are already 100 years behind here in tackling neurological problems. So we cannot afford to wait for the completion of all of the goals of the study. So any finding we have after we do what we call periodic analysis, we have a team of bio-informaticians, data scientists, statisticians and researchers who are even as we speak now, looking at 230, 240 patients, volunteers data, that were acquired over the last seven months and trying to understand what are we seeing. Are we seeing something that we can learn from, even though none of them has developed a disease yet?

Dr. Imad Najm: And we hope within next two, three years, when we have 5,000, 6,000 individuals with two-, three-years of follow up, we may have some early findings or early clues about what some of biomarkers may look like and where are they coming from. Is it from the blood, from the stool, from the MRI? And then, to share these findings in scientific journals. And we hope to use some of this data that we will be generating to apply for funding from government agencies and in particular from the National Institutes of Health (NIH).

Annie Zaleski: Now, as the study progresses, then, obviously it's supposed to be 20 years, is there the possibility of potentially extending it if things are going well or the data that is just so exciting and groundbreaking that it would be a shame to just stop?

Dr. Imad Najm: We hope that the study will progress as long as there is a question about a particular neurological disorder. I think our dream here and our plan is that the study will transcend generations and will enable not just this generation, but future generations to continue it as needed to build on it. But as importantly, to be able to use the data that this study would have collected for many years before. Now, we think, and we hope that some of this data that we are collecting now, for example, an MRI scan, we are able to analyze it with the technology of 2022.

Dr. Imad Najm: We hope and we think that in 2050, for example, there will be much better ways to analyze the same images that you and I and all the experts are looking at now. And maybe get much more information from the same data that we have now and build on this in the process of early diagnosis and curing neurological disorders. So we hope that this study will never stop til every neurological disorder in particular of old age is tackled and hopefully treated and cured.

Annie Zaleski: And that goes back to what you mentioned earlier, that artificial intelligence and technology in that area has evolved so much and is really helping inform the study. And that's exciting too because in five years, who knows what will even be there that will be at our fingertips to be able to analyze this data or gather data. That's very exciting.

Dr. Imad Najm: Yeah, certainly it is.

Annie Zaleski: Well, is there anything else you want to add, then, or anything we haven't covered that you want to mention?

Dr. Imad Najm: Yes, I would love to state something that I think as society we have to be aware of. We all suffer from it when we have one of our own, developing one of these neurological diseases. A friend, a father, a mother, a sister developing a stroke or been diagnosed with multiple sclerosis. Or a father who just was diagnosed with Alzheimer's. And once we have this diagnosis, it's very close and personal to us and we all feel that we lost somebody, although this person is front of us still.

Dr. Imad Najm: So as a society, we have to start to think, do we want to plan on building nursing homes for the next 50 years to take care of crippling neurological disorders, or do we want to try to understand the brain better and develop the cure for tomorrow? We have to start today. As Cleveland Clinic, as a neurological institute, we are making the first step — and we hope this will create excitement all over the world and many institutions will bend together in order to fasten the process of untangling the reasons or the causes or mechanisms of neurological disorders and the process to cure them and prevent them from happening all together.

Annie Zaleski: And I'm glad you pointed that out because the emotional side of being a caretaker for someone or knowing someone can take a toll. And the fact that this study might do something to alleviate that or offer some hope to people — I mean, that can't be underestimated. Just the importance of that.

Dr. Imad Najm: Yes.

Annie Zaleski: Well, I want to thank you so much for being here today. This has been such a wonderful conversation and so interesting and I'm so glad this work is being done.

Dr. Imad Najm: Well, thank you for having me again.

Annie Zaleski: For more information about the Cleveland Clinic Brain Study, visit clevelandclinic.org/brainstudy.

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