Bonus clip from Tales of a Hijacked Brain, with Dr. Sara Manning Peskin
In addition to her writing, Dr. Sara Manning Peskin is a clinical researcher in the field of Alzheimer’s and other forms of dementia.
In this bonus segment, Dr. Peskin discusses some wide ranging issues related to dementia, including experimental drugs for treatment, testing for genetic markers, and preventative measures that, in her opinion, are not worth the money.
Phil Stieg: I know it’s not what your book is about, but I guess I have to ask you because I know there’s a number of people out there marketing and making a business out of prevention of Alzheimer’s. We got to treat this when you’re 30 and all the paranoid New York 30-year-olds are running to these, flocking to these, individuals to stave off the risks. What’s your take on that?
Sara Manning Peskin: Yeah, that’s been a business for centuries and for the most part, most of the stuff, essentially almost everything that you can get over the counter, is probably not worth purchasing. The big one we get asked about the most is Prevagen and what we tell patients is essentially go out to dinner instead. But if you have an invention, then hire their marketing firm, because that seems to be the most incredible marketing firm I’ve ever seen, that they get lots of people to buy it. So there’s some brilliant minds behind it, but it’s not the scientists.
Phil Stieg: Everybody thinks that dementia is Alzheimer’s. But there are other forms of dementia as well, correct?
Sara Manning Peskin: Yeah, exactly. That’s, to be honest, in clinic, the biggest question that we get is, what’s the difference between dementia and Alzheimer’s? The reality is, when we think about these diagnoses, we think about them on two levels.
The first is, what does it look like when someone goes about the world? What are they able to do or not able to do? And dementia just means there are things that they can’t do because of memory and thinking problems. And the connotation is that it’s something progressive, but it has nothing to do with what’s actually causing it at a molecular level. What we then ask is, if I took a piece of this person’s brain out and I looked at it under a microscope, what do I think I would see? What do I think is going on at the molecular level? And that’s where all those others diagnoses come in.
So Alzheimer’s disease, what it really means, is that there’s buildup of two particular proteins in the brain. Frontotemporal dementia is build up of different proteins in the brain. Lewy body disease is another one that’s a common one. That’s one where people will come in and say, I’ve been seeing these people and animals, and I know they’re not real, but they look very vivid. So they’ll say, look, I saw a rabbit run across the floor of the clinic just now. So they have these wild hallucinations, and that’s caused by a different protein. And the other sort of very common one is called vascular dementia. And that’s caused by clogs in the blood vessels in the brain. And that one’s a little bit harder in most cases to pin down on one molecule.
Phil Stieg: Tell us a little bit about Huntington’s disease.
Sara Manning Peskin: So Huntington’s disease was first described by Dr. Huntington, who was this sort of country doctor on Long Island, and he grew up following his father, who was also a physician. And he noticed that his father would treat these families that all seemed to have the same condition, where their limbs would start to get, they would sort of writhe, almost like they’re electrified, and they would get an early onset cognitive change. They would get dementia early on, and they often would have these sort of wild mood disorders before that even. And Huntington sort of gathered his sort of reflections on it. And there was another condition at the time that affected kids. And Huntington’s basic idea was, I think this might be a different thing. And that was his big contribution.
So for a long time, not that much was really known about the disease or done about the disease. We figured out that it was probably genetic, but nobody knew exactly what gene was causing the problem.
And then Nancy Wexler came into the picture, and she was a highly educated woman who was just finishing a Fulbright scholarship, and she was on vacation on a beach in France. And her father called and said, “Nancy, could you come home for my birthday?” And she was very smart and said, something’s up. My dad’s not that sentimental. He wouldn’t normally call me home for his birthday. Something’s going on.
So she was suspicious off the bat. And sure enough, she goes home. Her sister came in as well, and her dad basically sits both of them down on the couch and says, your mother has Huntington’s disease.
Nancy had actually known that the disease was sort of in her family, but the thought that she’d been told was that it didn’t affect women. And so she was surprised. And pretty quickly, she essentially overhauled her career to say, I’m going to focus on this disease that I’m now at risk for, because what her father had said, which is right, was that she’s now at a 50% risk of developing the disease. And so, along with her dad, they start running these workshops for scientists. And their basic premise was that in order to solve the disease, you have to find the cause. And to find the cause, you need to get people involved from lots of different areas of science.
And so they had these workshops and there were rules like you could only have ten or 15 people at the workshop and you couldn’t bring any prepared slides because you don’t want people relying on their old tropes. You want something that’s sort of novel and collaborative.
And sure enough, at one of the workshops they talked about this way of potentially finding the gene that causes Huntington’s disease. It was extremely controversial. So people were sort of lunging at the blackboard to basically say either this is a great idea or this is a terrible idea, it will take forever.
Ultimately Wexler is convinced that this is worthwhile to invest in. And so she starts gathering people to work on it and they gather some other people. And what they initially thought would take about a decade, took about three years.
So they had this groundbreaking paper in the late 80s that basically said the gene that causes Huntington’s disease is located on this part of chromosome four. It was a huge, huge development. It was the first time that a gene had been located that way. So it actually paved the way for hundreds of other genes to actually be found within the genome.
It also started off the technology for genetic testing for these types of conditions. So it really paved the way for people to do what they can do now, which is, if you have a family history of Huntington’s disease and you want to know whether you’re likely to get it, you actually can go get genetic testing even when you have no symptoms. And they can tell you whether you think whether you’ll have it if you live long enough or not.
Wexler herself actually never took the test. She basically said, I realized I had a lot more to lose by taking it than I had to gain. So she never took it. And ultimately, years later, quite recently, she sort of come out and said, look, I’ve developed the disease and her sister didn’t. So they really fell in that 50 50 range.
Phil Stieg: The uplifting part of it, however, as I saw it, was that these people that have either mutations or abnormal genes, now with the advances in in vitro fertilization, you can still go on and have a family and not worry about transmitting this disease along your family line.
Sara Manning Peskin: Yeah, that’s one of the, because we talk a lot to people about genetic testing, because a lot of the diseases that we study are adult onset genetic diseases. So people have been carrying these abnormal genes for their whole life and for some reason in their forties, fifties, sixties, seventies, it causes them a problem.
One of the big things about genetic testing is sometimes it allows you to enroll in research studies, but in some ways the biggest one is for these people who have children who are now in the process of making their own families, if they can figure out whether there’s a gene or not. It’s exactly what you said you can use IVF. So you take a sperm and egg, you merge it in a laboratory, it divides, gets bigger and divides and gets bigger and divides. And then eventually you take a few cells away and you check. And if they have the genetic mutation, you don’t use that embryo. And if they don’t, you put them back in the uterus and you grow a baby that’s genetically related to you but doesn’t have the disease, which is this incredibly powerful technology.
Phil Stieg: And that was the one message I wanted to get out there, is that there may be nothing in it for you in terms of early testing, beyond the fact that if you are in the reproductive period of your life, IVF is a reasonable alternative so that you can have a family, if that’s what you desire.
Sara Manning Peskin: Yeah, it’s one of the most empowering things, I think, for people.
Phil Stieg: In the patient population that you deal with that’s losing their memory? Is it loss of their ability to pivot and to be flexible, or is it truly their loss of memory?
Sara Manning Peskin: So it depends actually. And we actually can parse that out in cognitive testing. So your ability to be flexible is more what’s called executive function. So that’s things like you step out of the grocery store and you meet someone on the street that you didn’t expect to see and you have to pull up their name, or you hit a detour in your hometown and you have to navigate around it without GPS. So that’s all executive function versus memory, really.
Pure memory, you actually can test a little bit differently and so we can actually separate it. And there are different diseases that tend to cause problems with each. So classically Alzheimer’s disease first affects that pure memory problem, but people’s executive function may actually be okay. So you could probably very early on in the classic cases of Alzheimer’s disease, you could give them a question that requires sort of some careful sort of calculations and multitasking and thought, and they may very well be able to do that. But when you ask them three weeks later what they did, they don’t know that there was a question.
Whereas someone with frontotemporal dementia, classically early on, they know exactly the date and the time. They know what they did last week. They know what they ate for lunch yesterday. But if you ask them to tell you the similarities and differences between a turnip and a cauliflower, they might not be able to give that abstraction of realizing they’re both vegetables.
Phil Stieg: So day in and day out, you are dealing with people with dementia, and I’m presuming that you abide by your Hippocratic oath and you want to do no harm, but you also want to give patients hope. So what do you do for the hope component for patients with dementia?
Sara Manning Peskin: So the biggest thing is that most of the diseases I study are slowly progressive. So that sort of kuru type thing where you die within a year, that’s rare. Most of the conditions I study, they go on for years. And so what I partly try to emphasize is, this is not a terminal cancer. I tell folks, don’t go out and spend all your money. You will live with this for a long time.
And there is joy after diagnosis. It’s not that you get a diagnosis of a neurodegenerative disease and there’s no more joy in life. That’s not the case. All it means is you have to find different avenues to be able to do things that you want to do, and you may have to change the things that you’re able to do.
Phil Stieg: Do any of the medications that are available? Do they slow it down at least, or do you just not really think medication is the answer at the present time?
Sara Manning Peskin: So it’s a good question. The cornerstone, a lot of it is behavioral modification. So it’s things like, if you have someone with dementia who’s convinced that their dead father is going to be coming for dinner, then by all means, let them set the table. That’s okay. So some of it is just sort of saying, if it’s not life threatening, you don’t need to remind the person that they actually have a problem. So some of it is that type of stuff, and I should say the landscape sort of is just changing. So right now there are some medications that help sort of cover up the symptoms, but they don’t actually change the underlying pathology. They don’t change the underlying disease for the most part.
Phil Stieg: So when you refer to the pathology. My mother had Alzheimer’s and she became angry, so she had these affective changes. I’m presuming that’s what you mean is you prescribe medicine to help with those issues?
Sara Manning Peskin: Right. So medications can help with that stuff, but at least until very recently, we didn’t have medications that actually got rid of the proteins that we know are the trademarks of Alzheimer’s disease. And very recently, we think that may have changed.
So the disease itself is characterized by build up of amyloid and tau proteins. And amyloid builds up about ten to 15 years before you have symptoms. And for that reason and a few other reasons, a thought in the field has basically been, look, if we could get rid of amyloid maybe we can actually not just cover up the symptoms, but actually change the course of the disease, which would be a huge development in the field of dementia in general.
Phil Stieg: Is there a study going on looking at that now?
Sara Manning Peskin: So there have been lots. We’ve spent billions of dollars of your money, all of our money has been spent on trying to make that work. And for the longest time it didn’t work. But now we actually have the most powerful drugs we’ve ever had that actually really do get rid of amyloid proteins. You can take a picture of someone’s brain and show that they have amyloid. You give them the drug, take a picture again, and it’s gone. And what’s now been sort of in the press a lot is a drug called Lecanimab that’s very effective at cleaning up amyloid. And the company that makes it did this relatively large trial with about 1800 people, and they had people take the drug for a year and a half. And after a year and a half, the people that were on the drug, they still declined, but they declined by a little bit less.
So there are two ways to look at it. One is the change in the effect size was quite small. So you could say it’s very pessimistic because we now have this drug that really gets rid of amyloid, but it doesn’t even do that much. On the other side, you could say, look, the effect size was small, but it was statistically significant. The people had only been on it for a year and a half and the effect size got bigger over time. So maybe if you’re on it for three years, it’s a bigger effect size. And the other big thing is this is the first time we’ve ever done this in Alzheimer’s disease. We’ve actually had a disease modifying therapy.
Phil Stieg: So you are recommending that drug.
Sara Manning Peskin: So I will say essentially the approval it got was called accelerated approval. So essentially it’s not covered by anyone. Penn is not prescribing it right now, or it’s not offering it right now.
Phil Stieg: How expensive is it?
Sara Manning Peskin: It’s $26,000 a year. And the calculation has been that the more cost effective price would be somewhere more in the sort of I want to say it was sort of the $6,000 to $8,000 a year. And so it’s very controversial.
But the thought in general in the field is for people who look exactly like the people in the trial, who are not at an increased risk of developing side effects. It would probably be reasonable to use, with the thought that people who choose to do it need to know this is a new drug. It’s very cumbersome to take. You have to take it’s an infusion every two weeks. And so there’s a concern of making people feel like they’re sicker, because if you’re going to an infusion every two weeks, you certainly feel medicalized. And that we don’t know if that effect size keeps getting bigger or not.
So if I said you have to get an infusion every two weeks and you’ll decline 25% slower, but you’re still going to decline, you might say that’s not a quality of life that I want. But if I said after four years, the disease actually stops in its tracks and if you start it early enough, you may actually never have a big problem that might change things.
Phil Stieg: So you do believe in prevention?
Sara Manning Peskin: I believe prevention is possible.
Phil Stieg: So, last question, what is the most promising thing, other than this new drug that’s been kind of approved? What is the most promising area of research in the dementia diseases that you’re following closely?
Sara Manning Peskin: I think the biggest area for us, and this might be just because of the niche that I’m in, is these targeted solutions for genetic causes of dementia. So even at our center, there’s a genetic cause for frontotemporal dementia. And we actually have literally three clinical trials running for this one genetic cause. And it’s rare, but it can serve as a model for solving these other adult onset genetic diseases.
From what I’m involved in, that’s the most promising thing. It’s these patients where they show up, they think that this is caused by back pain, they think this is caused by not enough sleep or whatever else, and it turns out it’s caused by a single genetic mutation. And then you go to your pharmacy, you take something off the shelf and whether it’s a gene therapy or something that targets a protein, it’s specific to that patient.
I think that has to be how we solve this stuff.