Learning About the Great Unlearning

Transcript Generated by AI.

Announcer: 0:00

Welcome to MedEvidence!, where we help you navigate the truth behind medical research with unbiased, evidence-proven facts, hosted by cardiologist and top medical researcher, Dr. Michael Koren.

Dr. Michael Koren: 0:11

Hello, I'm Dr. Michael Koren, the executive editor for MedEvidence! And we get a lot of questions here at MedEvidence, and one of the things that comes up all the time is about memory issues. And I'm so fortunate to have an expert in memory issues, Dr. Reza Bolouri, who's joining me here in the studio. And we're going to have an exciting conversation about memory issues and also talk about clinical research in the memory area. So, Reza, thank you so much for being part of our MedEvidence family.

Dr. Reza Bolouri : 0:42

Thank you so much for inviting me. Great to have you.

Dr. Michael Koren: 0:45

Yeah, so let's just start. We like to start by just getting to know each other, you, me, and the audience. So tell us a little bit about your background. You had a little bit of a non-traditional way that you became a memory physician. So why don't you let everybody know how you got there? And and and by the way, uh Reza is one of really the national experts in memory and in research in the memory area. So again, thank you for that. But how'd you get there?

Dr. Reza Bolouri : 1:09

Thank you. Actually, after medical school, I um was uh studying for my boards, being a foreign medical graduate. So I was looking for a job and I stumbled into this um um neurology practice that was uh a general practice, but they were they had started doing some clinical trials on Alzheimer's disease. So I was hired as a research coordinator.

Dr. Michael Koren: 1:33

Wow.

Dr. Reza Bolouri : 1:33

And um I that's how I got my feet wet and started looking at studies uh when we really didn't have much uh knowledge about what was going on with Alzheimer's disease, what was happening, even the amyloid hypothesis was just growing. And eventually uh through the years, after uh several hundred studies uh began to understand Alzheimer's disease, became very interested in Alzheimer's disease and therapeutic areas. And uh at some point I started my residencies after passing my boards, did uh uh psychiatry and uh subsequently neurology, and uh settled down in Charlotte, North Carolina, opened up my own practice after working for a hospital for about two years, then started a general practice and eventually cognitive neurology, and then subsequently went back to clinical trials and doing research.

Dr. Michael Koren: 2:31

So interesting. So you really started from the ground up Even before you were a practicing physician in the United States, you were actually learning research.

Dr. Reza Bolouri : 2:40

That's correct.

Dr. Michael Koren: 2:40

That's really, really cool. I love that. Great story. So tell us a little bit more about how your practice developed. I know that you have a unique model of reaching out into the community to help people that may have concerns about the memory.

Dr. Reza Bolouri : 2:53

Well, actually, given my background in Alzheimer's, I became extremely interested in geriatric neurology and specifically in uh cognitive neurology. And um we do know that the majority of the cases of dementia happen to be Alzheimer's disease. That's why a lot of folks uh interchangeably use Alzheimer's and dementia, whereas they're not exactly the same thing. So I um um focused on uh cognitive neurology. Dementia established uh a major population of folks in the Charlotte area who had memory disorders, and then uh my practice began to focus more in the dementia area, and then my background in research, we decided to go ahead and restart our clinical trials. So we've been very successful over the past 20 years in not only the general practice, but also our uh research grew uh uh rather rapidly. And um uh we've done over 200 studies just in the past two years, uh 20 years, sorry. And um uh we we are I'm proud to be um uh one of the uh investigators involved in all the drugs out there for Alzheimer's disease, starting from the symptomatic therapies and newly approved uh disease modifying drugs. And we continue uh that path and um we are introduced to uh much better, new and improved drugs, which we are working on right now.

Dr. Michael Koren: 4:20

Yeah, and that's so satisfying. Actually, one of the great joys I get as a clinical investigator is to be part of these programs that result in products that help people's lives. So there's nothing better than that. Yes. So let's let's break down memory issues for the public. As you mentioned, you alluded to the fact that Alzheimer's is a subset of dementia issues and memory issues, but there's a lot of confusion out there. So let's start with a patient that's concerned about his or her memory. They come to you, how do you break down this particular person's uh concerns from something that's either real or not so real, quote unquote. And how do you figure out if it's Alzheimer's versus another form of dementia?

Dr. Reza Bolouri : 5:03

Well, the best way I usually explain that to my patients and their families is um dementia is not a disease, it's a syndrome. And uh basically what that means is, for example, we have heart failure, we have liver failure, kidney failure, and so on. And dementia is nothing but a brain failure. So if you could just uh um I describe it that way, it's a brain failure. So when someone comes to me with any kind of a cognitive issues, the first thing I want to do is get a good history, do a good physical examination, do some preliminary workup to distinguish uh the type of dementia we are dealing with. For example, someone who is drinking 20 years every day, all day, that's alcoholic dementia. Okay. When you do an MRI of the brain and you see a bunch of strokes, that's vascular dementia. If somebody is exhibiting some Parkinsonism, it could be a Parkinsonian dementia or Lewy body dementia. A patient starting with the language problem, behavioral problems, it could be frontemporal dementia. Through some assessments and good clinical work, we determine exactly what kind of dementia that is.

Dr. Michael Koren: 6:16

Interesting. So just to help people, you you you threw out a lot of stuff there, which is great. But for example, uh Parkinsonian dementia would be associated with other elements of the Parkinsonian syndrome or disease, including like stiffness. Maybe mention some other things that would be associated with so people can understand the difference between that and Alzheimer's.

Dr. Reza Bolouri : 6:36

Well, you know, uh once once you begin to learn about the dementias, is you you're able to distinguish the differences. However, uh uh, for example, Parkinsonian dementias, uh there are two types. Uh there are several types of Parkinsonian dementias. For example, there are folks who have established diagnosis of Parkinson's disease, and later in the course of their disease, they develop dementia. That's called Parkinson's disease-related dementia. Whereas other types of Parkinsonian dementias, the Parkinsonism and dementia come at the same time or within a year from each other. So that's different than a well-established Parkinson's disease, whereas uh Parkinsonian dementias that are not Parkinson's disease-related dementia, they do not exhibit all the signs and symptoms of a typical Parkinson's disease.

Dr. Michael Koren: 7:26

Got it, got it. So taking a step back, because this is a common question that I get, even in my cardiology practice, is when people are having difficulty with their memory, how do you distinguish changes in your memory and maybe your mental acuity as you get older versus an actual disease?

Dr. Reza Bolouri : 7:46

Well, I'm asked about this question a lot. Uh, there is a phenomenon uh uh called age-associated memory impairment. In the old days, we used to call them senile dementia, presenility, hardening of the arteries, and a whole host of things. We no longer use those derogatory terms. Uh so we call it age-related memory problem. How do we distinguish the age-related memory problem from Alzheimer's disease? Is as we age, just like everything else, we slow down mentally and physically. Age-associated memory problem, the folks begin to have some short-term memory problem. They go to a room wondering what they went there for, and then uh slow down in many respects in their responses, in their activities. However, they do not progress. They remain the same and fully functional. They're 90-year-olds, 100-year-olds who are still doing their things, but yes, they have lapses of memory, the senior moments. Whereas with Alzheimer's, the folks who are transitioning to Alzheimer's, they begin to lose the ability of the learned processes, learned uh habits, learned activities. That's why we call it a great unlearning. And these are the folks who have learned, they have raised families, they've educated, they worked, and eventually they lose the ability to drive, to make decisions, to pay bills, and that's why you can tell the difference versus progressive o r stable form of memory impairment. And that's that's that that's how we can tell the difference.

Dr. Michael Koren: 9:22

Got it. Is there something you can learn about that difference by doing mental status testing? How good is mental status testing at determining who has this more ominous progressive form versus people that may just be getting a little slower because of age?

Dr. Reza Bolouri : 9:40

Well, I mean, the science has advanced. I mean, now we have ways to really tell if someone is developing Alzheimer's disease, which we can go to when we talk about research. But generally, uh, a good clinical practice, a good uh practitioner observes the patients for a while to see who is declining and who is not. The best source of information is patients' family. Okay. They tell you he or she is not the same. He forgot, uh he got lost driving, he forgot to pay a bill, he made a bad decision, he got scammed uh online. Uh those are the things that raise the flag of something else is going on. And besides, when we talk about dementia, when we talk about memory memory, it's not just memory. It's memory, problem solving, decision making, planning, organizing. Everything is affected. It's not just memory. Memory is the first thing we notice, but everything else uh happens.

Dr. Michael Koren: 10:34

So interviews with family and the patient you think is more valuable than some of the formal cognitive testing, or there's a role for both?

Dr. Reza Bolouri : 10:42

It's a combination. There's a role for both. Of course, we we do rely on some of the testing, but there's there's nothing best better than a good history from the patients, from their families. They tell you everything that's going on. And you know, if you're experienced, you can catch on as to what's going on. And then, of course, you know, you order your general uh workup, MRI, blood work, and a whole host of things. But basically, I personally rely on that history and physical exam before anything else.

Dr. Michael Koren: 11:12

Fascinating. Interesting. So tell us a little bit more about Alzheimer's as a percentage of all forms of dementia, and then uh walk us through what the definitive test is for Alzheimer's.

Dr. Reza Bolouri : 11:25

Well, like I said earlier, the reason folks use the Alzheimer's and dementia interchangeably because 60 to 80% of the dementias happen to be Alzheimer's disease. And for that reason, besides the good history and physical exam and some of the initial assessments, now we have sophisticated methods, uh, brain PET scan, amyloid PET scan, Tau PET scan, blood biomarkers, and uh and a genetic test to check for susceptibility gene for Alzheimer's disease. Now we have become much more uh sophisticated in uh actually identifying the Alzheimer's versus non-Alzheimer types of dementia. In fact, now uh most of the research is focusing on prevention to identify the patients who are at risk of developing Alzheimer's disease 20 years from now.

Dr. Michael Koren: 12:16

Interesting.

Dr. Reza Bolouri : 12:16

So that's that's that's how we have uh advanced, whereas we are identifying folks who will be developing Alzheimer's disease 20 years from now. The changes in the brain have started, but they're functioning normally. They're working, they're raising family, they're making decisions without any problems.

Dr. Michael Koren: 12:34

So fascinating. So tell us a little bit about um the definitive test that gets people involved in a clinical trial. What you usually have to find for people to be able to enroll in a clinical trial.

Dr. Reza Bolouri : 12:48

Well, for the longest time, you know, I'm sure a lot of folks have heard that we used to say, you know, after uh a patient passes, you know, you do the pathological evaluation of their brain. We no longer do that. So the the the evolve uh evolving um uh diagnostic workup initially was uh brain PET scan, just a FTG PET scan to distinguish between Alzheimer's, frontotemporal dementia, Lewy body dementia, and so on. But with the advent of the amyloid scans, now we can do amyloid PET scans where we can actually see the amyloid that lights up in those images. We can tell.

Dr. Michael Koren: 13:28

That's interesting.

Dr. Reza Bolouri : 13:29

However, unfortunately, amyloid PET's uh are very expensive. And a lot of insurance companies, even Medicare, was not on board with that, $10,000, $15,000. So then they we resorted to spinal fluid analysis, where if the theory, the theory goes if those proteins are sitting on the brain, there's not enough of them drained in the spinal fluid. So by those measurements, we could come to a fairly close approximation of the development of Alzheimer's disease. Over the past five years, now we have blood biomarkers. Uh recently, uh Lumi pulse uh is the most sophisticated blood test that uh can accurately diagnose Alzheimer's bit uh 90 uh uh percent sensitivity and specificity. So, with that in mind, now rather than the PET scan or spinal fluid, where a lot of patients don't like it because of the pain and so on involved. So, with a simple blood test, we can actually determine if somebody uh is developing Alzheimer's.

Dr. Michael Koren: 14:32

Interesting. So, how does that blood test at 90% accuracy compare with an FDG, FDG PET, which is looking at glucose metabolism in the brain for people that are not familiar with the terminology?

Dr. Reza Bolouri : 14:43

Well, you know, uh understanding Alzheimer's, uh we do know that the folks with diabetes are at highest risk of developing Alzheimer's simply because their glucose dysmetabolism is one of the biggest culprits in Alzheimer's disease. For for the longest time, the the metabolism of glucose through the FDG PET, we were able to determine if there is a metal decreased metabolism in the temporal areas, in parietal areas. If it was temporal and frontal, they would be frontotemporal.

Dr. Michael Koren: 15:13

If it was occipital, and frontal here and temporal here, just for people that-

Dr. Reza Bolouri : 15:17

-frontal, temporal-

Dr. Michael Koren: 15:18

-use to these terms.

Dr. Reza Bolouri : 15:20

Occipital, which is uh basically the Lewy body. But what happened is that was nonspecific. It was giving us some ideas, Just like MRI shows some atrophy, for example. However, with the with the amyloid, now we can actually uh inject a tracer where the amyloid lights up.

Dr. Michael Koren: 15:39

Interesting.

Dr. Reza Bolouri : 15:39

And that's what we know. Yes, that's amyloid that's sitting there. Uh now with the tau, we can tell that the tau protein is sitting in the brain. So those are the markers that are over above a 95-96%.

Dr. Michael Koren: 15:54

Fascinating. Okay, so we diagnosed somebody with Alzheimer's dementia. Tell us about the therapy. I know there are some old school drugs that we've used. Are they still being used? I know there's some really interesting research findings that have led to new approvals. So why don't you break that down for everybody?

Dr. Reza Bolouri : 16:10

Yeah, I I remember when I was a research coordinator um uh in um Miami, initial uh medications were focusing on um cholinesterase inhibitors. And uh because the cholinergic uh theory was out there, we we did know that cholinergic deficiency caused Alzheimer's disease. And it's interesting how it came about. The folks who are using scopolamine patch for the seasickness, they were beginning to become forgetful. That's how it all came about. They realized the cholinergic therapy. So a lot of companies, a lot of the science, scientific community began to focus on cholinergic uh therapy. So um the body cannot uh metabolize choline. So they found indirect ways of finding how we can increase the acetylcholine. So indirectly, by inhibiting the enzyme acetylcholinesterase, we were able to increase the amount of choline in the body. So that's when anticholinesterase inhibitors like donepezil, rivastigmine, galantamine came about. And eventually, uh the first one uh which was tacrine in 1994, that was approved, and the donepezil in 1996. Those were the symptomatic therapy. They were providing some symptoms for uh a year or two, or maximum of three years, and then they would become less efficient because there was less cells to uh you know uh rescue. Right. So eventually uh memantine was approved. We did work on the 90s in 1996, it was approved in 97, it's a different class of drug, it's an NMDA receptor antagonist. So we had nothing until about 2020, 2020, 2021, where the anti-amyloid antibodies began to gain popularity.

Dr. Michael Koren: 17:57

It's about 20 years of not a whole lot of activity.

Dr. Reza Bolouri : 18:00

There was nothing. So in the clinical practice, we couldn't really offer anything beyond those symptomatic therapy. One of the things I loved about my research and practice is beyond the symptomatic therapy, I was able to offer disease-modifying drugs to my patients. And that's where the research comes, and it makes it much more interesting because you know, once you have done what you could with symptomatic, then you're able to offer your patients clinical trials, research uh uh medicines which are beyond the symptomatic, those called disease-modifying drugs.

Dr. Michael Koren: 18:34

Absolutely. So, where do we stand with anti-amyloid drugs and disease modifying drugs? Do we have do we have the magic bullet yet? Or what what should we looking for? What what is your recommendation in terms of what people should ask for at this point in terms of how far we've progressed?

Dr. Reza Bolouri : 18:50

Well, definitely we we uh have been able to slow the progression of the disease. I think that's a that's a major victory as far as I'm concerned. And um uh there there was four that that that was uh uh came out, and the first one, unfortunately, because of some potential side effects, did not pan out. However, right now the two most successful anti-amyloid antibodies are Leqembi or Lecanemab or Kisunla or Donanemab. Those two drugs are available. So physicians, not only the researchers, not only the neurologists, a lot of physicians can offer it, but they do require very careful monitoring because of potential side effects. So, having said that, right now, the drugs that we are testing are the new and improved anti-amyloid and anti-Tau antibodies that we are working on, which I believe within the next uh few years, we're gonna have a combination of anti-amyloid and anti-Tau antibodies to really put a dent in the course of the disease. However, a lot of people ask me, when are you gonna find the cure? Uh uh, my the best answer I can give is in order to find a cure for a disease, you have to find a single etiology for that disease to be able to tackle. Alzheimer's is not caused by one thing. Alzheimer's disease is caused by a whole host of bad things that happens in the brain. So are we gonna be able to tackle every single one? Probably no, but I anticipate a cocktail of medicines are eventually really going to put a uh stop to the progression of the disease because just like HIV, right? You know, in the beginning, when I was in medical school in the 80s,

Dr. Michael Koren: 20:33

It was a death sentence.

Dr. Reza Bolouri : 20:34

Death sentence. But now people are living with a good cocktail, normal lives. So I'm hoping for that for Alzheimer's medicine.

Dr. Michael Koren: 20:40

Interesting, very, very interesting. So, what's the next chapter for you? I I know that uh we talked a little bit about the fact that you've been doing this for a while and you're really interested in helping the next generation become great researchers. So tell us a little bit about that.

Dr. Reza Bolouri : 20:54

Well, actually, uh my philosophy in medicine has always been uh I there's a lot I don't know. But what I do know, I would like to go ahead and pass it on to the next generation, to the students, to the residents, to the new neurologists, new psychiatrists, new physicians who have an interest in tackling this devastating disease that's uh really affecting it's it's not only national, it's an international uh uh catastrophe that uh I would like to go ahead and pass on the knowledge and do the best I can to contribute.

Dr. Michael Koren: 21:25

Absolutely. So you have a bunch of uh mentees lined up to follow your in your footsteps as I understand it.

Dr. Reza Bolouri : 21:31

Yes, yes,

Dr. Michael Koren: 21:31

That's exciting. Reza, that was fascinating. That was a great, great summary of Alzheimer's dementia and a great summary of some of the research that has led to some affected products and really hope for the future in terms of potentially a cocktail that will turn Alzheimer's dementia into something that's very manageable, like HIV disease, as you pointed out. So those are really, really exciting things. Any final words you want to share with our audience with regard to uh your approach or what they should do if they're concerned about memory issues?

Dr. Reza Bolouri : 22:03

I mean, the the the best advice I can give to healthcare providers is uh be aware of memory issues. Don't just discount it, don't sweep it under the rug. Uh get some help, do some assessments. If you don't feel comfortable about doing that, send them to the memory specialists, send them to the memory centers, have them worked up because these folks deserve better than just, you know, it's just aging, what do you expect? I think I think that's uh when I do uh my talks to the primary care physicians and other neurologists, I I emphasize the fact that it's very important for us to be able to establish some kind of a criteria as part of the annual workup of Medicare, you know, wellness uh programs. And I think that's that's extremely important. I think uh I need to uh emphasize that we are doing some prevention trials right now. Prevention trials are for people who do not have memory problems, but they have the markers of Alzheimer's disease. Uh and uh one of the studies just got uh uh uh okay to continue, uh, which is very exciting. If that drug pans out and it's is approved, I think I'll be the first one to say after the age of 50, everybody should be screened for Alzheimer's disease to catch it early on before the symptoms begin.

Dr. Michael Koren: 23:16

Makes sense.

Dr. Reza Bolouri : 23:17

Because by the time you come with symptoms, several years has already passed.

Dr. Michael Koren: 23:20

Right.

Dr. Reza Bolouri : 23:20

So catch it early, that's the key.

Dr. Michael Koren: 23:23

Absolutely. Well, that's that's great insight. So thank you very much for sharing that.

Dr. Reza Bolouri : 23:27

Welcome.

Dr. Michael Koren: 23:27

So, Reza, give us an example of a patient that's been helped by the advances in pharmacotherapy for Alzheimer's.

Dr. Reza Bolouri : 23:36

Well, you know, the disease, the new disease-modifying drugs actually uh do dissolve these proteins in the brain. For example, the the newly diagnosed uh uh newly approved drugs that Kisunla and Leqembi, uh, we can actually measure the amount of protein that's been uh cleared uh by these drugs. And by that, in fact, at some point within a year and a half to two years, you can actually stop those because the clearance has been completed, where the brain almost has no more amyloid or tau protein. So that's quite impressive. That I I believe that with new and improved therapies with less potential side effects, we should be able to get this. I have many patients that have been following that in the past they would not survive beyond five or six years, ten years on, they're still communicating, they're interacting. So that's that's quite rewarding for me as a researcher.

Dr. Michael Koren: 24:31

And you see people that respond clinically that actually get better. Yes. Isn't that great?

Dr. Reza Bolouri : 24:36

Yes, yes. There are some authorities that actually believe Alzheimer's is a type 3 diabetes, simply because we do know that brain uses glucose as a metabol, as a fuel. So when there's not enough glucose or there is a disruption of the glucose delivery to the brain, brain is affected.

Dr. Michael Koren: 24:55

Right.

Dr. Reza Bolouri : 24:56

There are two types of Alzheimer's disease. There's an old onset, there's a young onset. Fortunately, young onset is a minority of the cases, and they happen to run in families almost in a form of autosomal dominant inheritance. There's a group in Colombia, everybody has Alzheimer's disease. Even children have Alzheimer's disease. Fortunately, young onset Alzheimer's disease is rare simply because it's a more malignant form of Alzheimer's disease. It happens in a younger population with significant behavioral disturbances. Um, but uh majority of the cases are the are the older type Alzheimer's. So if I'm gonna develop Alzheimer's disease, I don't mind in my 50s and 60s, I mind in my 80s. Got it. What happens is uh statistically, uh the Hispanics are at the highest risk of Alzheimer's disease.

Dr. Michael Koren: 25:47

Interesting,

Dr. Reza Bolouri : 25:48

-followed by the African Americans uh and then Caucasians. Okay. So uh why do why don't we have more uh Hispanics or African Americans simply because of the the uh availability of the healthcare uh and educational background to seek help? I think that's been amazing.

Dr. Michael Koren: 26:06

Are there any theories as to why Hispanics are at higher risk?

Dr. Reza Bolouri : 26:10

Well, um my theory is uh the folks in the minority community do not get the medical attention that they deserve for hypertension, for diabetes, for high cholesterol. And we know at the end of the day, all these brain disorders are vascular.

Dr. Michael Koren: 26:26

Yeah. It gets into something interesting, which is called the Hispanic paradox. So people of Hispanic ethnicity actually live three years longer on average than white people. And uh that's always an interesting little tidbit in the United States that we don't talk that much about. So there's some things that Hispanic populations are doing really well.

Dr. Reza Bolouri : 26:46

They have a closer family ties, having a Hispanic as a wife.

Dr. Michael Koren: 26:51

Well, that can be or they eat better or they are more physically active, but it's it's a it's an interesting paradox.

Dr. Reza Bolouri : 26:56

Yes.

Dr. Michael Koren: 26:56

So, Reza, a lot of my patients come to me and ask me, I'm really concerned I have Old Timers disease. So is it Old Timers or is it Alzheimer's? And why do we call it Alzheimer's?

Dr. Reza Bolouri : 27:08

Actually, uh a lot of folks uh since uh age happens to be the biggest risk factor for Alzheimer's disease, a lot of older folks develop Alzheimer's. So it's just, you know, some folks say it's Old timers disease or All Timers disease. In fact, the term comes from Dr. Alois Alzheimer, who was a German pathologist and had seen a patient uh uh who was a very young woman uh in her 50s. Uh the initial description of Alzheimer's change was a young onset Alzheimer's patient, um, which uh uh that's how the name came about. Uh Alzheimer's

Dr. Michael Koren: 27:47

So it's a relatively modern disease, only about 100 years old.

Dr. Reza Bolouri : 27:50

That's right.

Dr. Michael Koren: 27:51

Reza, it's been a delightful conversation. Thank you for being part of MedEvidence!

Dr. Reza Bolouri : 27:55

Welcome. Thank you so much for having me.

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