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- [00:00]
Dr. Luisa Nicola
Mom, can you tell me a story?
- [00:02]
Carvana Ad Narrator
Sure. Once upon a time, a mom needed a new car.
- [00:05]
Dr. Luisa Nicola
Was she brave?
- [00:05]
Carvana Ad Narrator
She was tired mostly. But she went to Carvana.com and found a great car at a great price. No secret treasure map required.
- [00:12]
Dr. Luisa Nicola
Did she have to fight a dragon?
- [00:13]
Carvana Ad Narrator
Nope. She bought it 100% online from her bed, actually.
- [00:17]
Dr. Luisa Nicola
Was it scary?
- [00:18]
Carvana Ad Narrator
Honey, it was as unscary as car buying could be.
- [00:20]
Dr. Kelly Casperson
Did the car have a sunroof?
- [00:22]
Carvana Ad Narrator
It did, actually.
- [00:23]
Dr. Kelly Casperson
Okay, good story.
- [00:24]
Carvana Ad Narrator
Car buying. You'll want to tell stories about. Buy your car today on Carvana. Delivery fees may apply.
- [00:34]
Podcast Host Announcer
Welcome to youo Are Not Broken, the podcast that challenges everything we've been taught about midlife hormones and sexuality. I'm Dr. Kelly Casperson, board certified urologist, author, and a leading voice in women's sexual and hormone health. Enjoy the show.
- [00:47]
Dr. Kelly Casperson
Hey, everybody. Welcome back to the youe're Not Broken podcast. Super excited to have my friend, Dr. Luisa Nicola. I feel like we met on stage. I don't know, we like, we don't even know where we met. And thank you for becoming on the podcast.
- [00:59]
Dr. Luisa Nicola
Thank you so much. I always admired you and loved you and I think that the day that we met I was really nervous and now I can call you my friend, which is so cool.
- [01:08]
Dr. Kelly Casperson
See how quickly that happens when you're a good, smart person, you're like sweet. You're one of the more well connected people in the universe.
- [01:18]
Dr. Luisa Nicola
Dr. Nicola, why do you say that?
- [01:21]
Dr. Kelly Casperson
You know everybody.
- [01:22]
Dr. Luisa Nicola
I mean, I try to.
- [01:23]
Dr. Kelly Casperson
You generally love humans, you love science, you love conversation. It just makes you very easy to want to. To be friends with.
- [01:30]
Dr. Luisa Nicola
I know. And I have a mission and you're part of that mission too. And I love that. And I love the human brain. And you have one of those, a really beautiful one.
- [01:40]
Dr. Kelly Casperson
Yeah, I want to keep it good. So that's what we're going to talk about today of like, how do we keep the brains braining in a good brain fashion. So tell me about, like, tell me about your schooling and your catch us up to like, why brains?
- [01:56]
Dr. Luisa Nicola
So I first started off with exercise physiology and then moved into a Master's of mathematics. Believe it or not, I was quite the mathematician. And that's actually where I got my first real look at algorithms and neural networks. And so my thesis really looked at like neural networks and algorithms. I then fell in love with the human brain. I saw my first cadaver at the age of. I think I was around 20. And I got to actually see a human brain. Inflation, obviously. Look at the coronal sections fell madly in love with it. I often say the human brain is my first love. And then after the masters finished, I was still. I think I was still around 21, 22. I moved into a Master of Medicine, and that was at the University of Sydney, Sydney Medical School, and then went on and did a doctorate in neurophysiology. So neurophysiology, for those of you who don't know, is a science subspecialty of neurology. And I have spent the last decade working in neurosurgery, and basically my main role in there is looking at two things. First of all, if we're going into a craniotomy or even a tumor resection or spinal surgery, ensuring that during the surgery the patient isn't paralyzed or stroking out, you can imagine a lot of people say, oh, doesn't the neurosurgeon know how to not do that? It's like, well, the brain is the most vascular, rich organ in the entire body, and just, you know, moving like a hairline away from where they're cutting or resecting could mean the difference between staying alive or complete paralysis, for example. And we now have EMGs to help us, guide us through that process. And it's a really, really amazing thing for patient outcomes.
- [03:45]
Dr. Kelly Casperson
I love that. I also love that you're correcting people when they're like, can't the surgeon just do it all, all at the same time? It's like, no, it takes a team in the operating room, people.
- [03:56]
Dr. Luisa Nicola
Yes. But also, my main mission now is to end Alzheimer's disease. And this is because as a neurophysiologist, when I was working, I think it was around 2016, I was working in the neurology wing and my entire mission. Then I got tasked with, Louisa, you need to be doing all of the EEG scans to pick up on something called mild cognitive impairment. And I didn't really know what that was. And we'll go into it. It's a pre dementia state. And I was just tasked with scanning all of these brains. I think I've done around five and a half thousand, six thousand brain scans since then. And I was picking up on early onset Alzheimer's disease, mild cognitive impairment. And every time I went to the attending and said, what does this mean? Why are we giving so many diagnoses of Alzheimer's disease? What can we do for these patients? His answer was, nothing, we can't do anything. They're just born like this. And that didn't sit well with me, Kelly. So I Just I. Ever since 2016, I've gone deep on publishing, first authoring a number of academic papers to understand why is it that 70% of all Alzheimer's disease cases are female? Why is it that Alzheimer's disease and dementia is the number one cause of death in Australia and the UK amongst women? And why is it that that all, like 95% of all Alzheimer's disease cases, why is it that they could have been prevented? So that's what I do know.
- [05:24]
Dr. Kelly Casperson
95% can be prevented.
- [05:26]
Dr. Luisa Nicola
Correct, 95%. And that's actually something I would caution that. I would say that it's around 98%, but there's only around 3% of all Alzheimer's disease cases that are 100% penetrant, you know, that are driven through genes. The rest, 90. Why? Why? Why do we have it? Because of lifestyle.
- [05:46]
Dr. Kelly Casperson
I mean, one might say the success of our lifespan, meaning when we were dying at average age of 47 because of blunt force trauma and infections and dirty water and all the things mammals in the wild die of, we didn't have this longevity of, like, the resilience of the brain. We have a lot of neuroplasticity and a lot of resilience and a lot of backup plans built into the system. But because we're not dying of everything else, and we are aging, is dementia and Alzheimer's and maybe neurodegenerative diseases in general a result of an extended lifespan, it doesn't mean that it's inevitable.
- [06:25]
Dr. Luisa Nicola
Correct. And it's so funny because that's when we can bring in the sex differences in this disease. But you look at this disease, and yes, we are living longer because of antibiotics, penicillins and vaccines, which have gotten us to the stage of the degenerative process of our brain, which is inevitable, by the way. The brain does age, but dementia is not part of the brain aging process.
- [06:49]
Podcast Host Announcer
Whoa.
- [06:49]
Dr. Kelly Casperson
That's crazy. I see people doing this repeatedly, which I'm grateful for, is people keep being like, women aren't getting dementia because they live longer. Women only live, on average, four years longer than men. And you don't. And dementia doesn't happen in the last four years of your life, between the ages of 80 and 84.
- [07:06]
Dr. Luisa Nicola
It's a disease of midlife.
- [07:08]
Dr. Kelly Casperson
Yeah. And it's a big myth that it happens because women live longer. Like, that argument falls apart so quickly. And I think the other thing, and I, I say this when I'm on stages of, like on that horrible, horrible Tuesday that you get diagnosed, you or a loved one gets diagnosed with dementia. It started happening 20 years ago. And that's very hard for people to get their head around because everybody thinks it's the day of the diagnosis. Now I have dementia and it's not black and white like the diagnosis got on the chart that day. And now you think differently about things because of that. But it started happening 20 years ago, which means we've got a lot of lag time. And when we look at prevention, we have to go back, we have to talk about mid life, 40s, 50s.
- [07:55]
Dr. Luisa Nicola
Yeah. And this is the question that is on my mind constantly. And I get asked a lot, why do you focus on dementia?
- [08:03]
Carvana Ad Narrator
You're young.
- [08:04]
Dr. Luisa Nicola
Why don't you focus on something more exciting like IVs and why can't it be sexier? I'm like, but it is sexy because it does happen in your 30s. I'm in my 30s and I'm trying to prevent all cause dementia and Alzheimer's disease now. Not because I've got an increased risk, which we'll go over, but I am, as a woman, I do have an increased risk, but because I know the prevalence of it. And if you don't take care of your brain now, there is no reversal. I know that there are some physicians out there claiming that they've reversed Alzheimer's disease. I'm transparently saying that in my opinion, there's no reversal, there is no cure. And getting the diagnosis of Alzheimer's disease or all cause dementia, we have to figure out what the difference is between those two. It's comparable to end stage cancer. When you are diagnosed on that horrible day, hopefully nobody will be but of pancreatic cancer, for example, we know that it didn't happen just then, but we know that it's very hard to come back from that. Why didn't we pick up on it at stage one? It's very hard to. It's very hard. We don't have the, the imaging right now to pick up on stage one pancreatic cancer, but when we pick up on it in stage four, there's generally a very short time course, you know, of how long you'll live after that. And it's the same as dementia. And people think that all cause dementia or Alzheimer's disease is just, oh, you forget your memories. No, it's so much more than that. And there is no coming back from it.
- [09:27]
Dr. Kelly Casperson
Can you break it down for people, the difference when we say Alzheimer's versus when we say dementia, what specifically about that disease makes it Alzheimer's and Alzheimer's was a physician who first described it, because people lump dementia and Alzheimer's into one thing. Can you just give us the 101 on that?
- [09:47]
Dr. Luisa Nicola
Quite simply, dementia is just the umbrella term that's used to describe the decline in our cognitive functions, cognitive functions of thinking, processing speed, visual acuity. These tend to decline as we get older anyway, especially processing speed, like speed of our thought, et cetera. That's just the umbrella term. But Alzheimer's, it's actually Alzheimer's. Dementia is the most prominent type of dementia. 70% of all cases of dementia are Alzheimer's disease. And we've got Parkinson's dementia, we've got dementia with Lewy bodies, we've got many different types of dementia, vascular dementia, which comes second after Alzheimer's. But Alzheimer's is very different in the sense that upon pathology, if you look at this on neuroimaging studies, we'll see the buildup of two proteins, and we've got the amyloid beta protein and then we've got the tau protein, and these two are distinct features of this disease. And there's something called mixed dementia, because you can see some vasculopathy as well. So it kind of crosses over with vascular dementia as well in some cases.
- [10:56]
Dr. Kelly Casperson
And people, I think, for the longest time thought that the tau proteins and the beta amyloid were the problem. Therefore, billions of billions of dollars were spent trying to figure out how to clear the brain of these proteins. And that's changing. There was an investigative journalist who published a book called Doctored, talking about some research fraud, but also just the amount of money at the end stage, right, being like, how can we get the tau out and the beta amyloid out and attack those proteins? And now, correct me if I'm wrong, but the theory is more that those are signals or waste products or landmarks, but they themselves are not the problem. And also, people can have those things and not have dementia.
- [11:39]
Dr. Luisa Nicola
You're completely right. It used. So Alzheimer's used to be the amyloid cascade hypothesis, where we saw this cascade of amyloid in the brain. And so we just thought that this was what's causing Alzheimer's disease. So then the FDA went and approved, you know, Leqembi, Aducanumab, all of these drugs, which is the controversial one you just mentioned, to go out and clear the brain of amyloid. And it turns out that even after clearing the brain of amyloid, cognitive performance didn't subside, like people were still. Still had Alzheimer's disease. So we're now moving into more of an era where we know that amyloid beta is not the villain. Amyloid beta is a antimicrobial peptide. It is actually a protective peptide. Peptide is just a protein, if you will, a breakdown of a protein. It is actually needed in the brain to protect us. Then we've got tau protein, and that actually lives in the axon of the actual brain cell. So what happens is, let me just, you know, for your audience, if you can imagine, like a tree, for example, inside the actual cell body of the neuron, we've got around 87 billion neurons, which each make around 5 to 10,000 connections. What happens is when we feel stressed or when we actually have a virus, think the chickenpox, think shingles, any type of virus. Your brain is surveilling that, okay? It's under constant surveillance because it wants to do two things, survive and reproduce. So anything that attacks those two things, it says, okay, we need to protect ourselves. So the neuron cell body itself starts to push out amyloid. Amyloid is an antimicrobial peptide. So it goes out into the cerebral spinal fluid and basically helps trap pathogens, if you will. It helps you against these cytokine storm. In the case that you have activated your innate immune system, you've been stressed, your immune system is down, we release amyloid and it goes out there to shield the brain. Now just stay on that for a moment because it stays out in the cerebral spinal fluid and it kind of interferes with the connections. I said we've got around 5 to 10,000 connections per cell. The amyloid sits out there in the middle of those connections. Okay? So we've got this sticky protein just getting in the way of those connections. Those connections. If we don't have a good connection between two neurons, then we see slower thinking. Oh, brain fog. I'm not feeling too good because the connections are not connecting. Now, tau protein is actually quite remarkable. It sits in there, it stabilizes the microtubules, the railway tracks inside the axon. Okay? It's there. And if that becomes hyper phosphorylated under stressful conditions, what happens is it actually breaks off of the microtubules. It stays in the axon, but it starts to form these tangles. Not indifferent to the amyloid plaques, it starts to form these tangles within the axon. And then what happens? Then you get the collapse of these microtubules and. And then the collapse of the entire neuron itself.
- [14:41]
Dr. Kelly Casperson
Good Lord. So compensatory mechanisms to a response that the body's sensing too much can lead to pathologic outcomes. Or less proper functioning of the neurons themselves.
- [14:56]
Dr. Luisa Nicola
Yeah, less proper functioning. And what we see eventually is, okay, let's just say we are still under attack, we're still under stress. And your brain has released. Your neurons have released all of this amyloid, and it's sitting there in the cerebral spinal fluid. It's still sticky. So then it interferes with the axons, it interferes with the connections. And then dementia and Alzheimer's disease is a network insufficiency. Your network is breaking down. So we've gone from having a cell that has 5 to 10,000 connections to maybe a cell that has 2,000 connections. Now you imagine that 2,000 times 87 billion is a smaller number than 10,000 times 87 billion. So the network. We have a network insufficiency. We start to. It starts at your brain is like, okay, I'm going to take a seat. It starts to come down like this. And that's why on neuroimaging studies, we don't see. We see more space between the skull, if you will, and the brain. We see it because the brain is decompacting and getting smaller.
- [15:58]
Dr. Kelly Casperson
So atrophy of the brain, white matter, hypo intensity.
- [16:02]
Dr. Luisa Nicola
Yeah. Why? Matter hyper intensity is. Yet these white matter lesions are occurring due to the breakdown of the axon itself because of the phosphorylated tau.
- [16:12]
Dr. Kelly Casperson
I think, you know, people want, especially on social media, people want things to be black and white. They want things to be yes or no. And there are so many things that impact brain health. And then what people will do is they'll be like, my, my mom smoked and drank and never got dementia, or my mom didn't do any of that and still got dementia. And I, I really want to emphasize to people the multifactorial because, again, the brain's pretty resilient. It can take some hits. It just can't take hit after hit after hit. But even some people who hit it really hard don't get dementia. Because I think people will use that as a way to dismiss science then because they'll be like, what do you know? My mom never exercised and didn't get dementia. They use this n of 1 to dismiss science, but that's not how science works. Science doesn't work by n of 1. Science works by, like, testing hypothesis and repeatable patterns and looking at big, big, big things and big data sets. Can you kind of speak to that on, like, helping people understand the complexity of this?
- [17:16]
Dr. Luisa Nicola
Everybody's individualized. And I love how you said the n of 1. Okay, but in the reverse. Right. We can have multiple studies on millions of people and yet you still have an N of one where all of those data sets actually doesn't work for this N of one patient. And I've seen. You've seen it too. And so it's so funny that people do choose the divide, like, oh, N of one here, you know, it's. And so I find that really interesting. But when it comes to, oh, my grandmother was drinking and she lived to 100 and she did this. That's great. Everyone is. This disease is very in favor of what sex are you? Are you male or female? And I mean, you know, at birth, do you have ovaries in a uterus? And that's the first thing. And then the second thing is, do you have the genetic mutations that involve this disease or the genetic risk factors that involve this disease? Because the data is so strong that women are disproportionately more affected by the APOE4 gene than men, they are actually at an increased risk, at a doubled increased risk than men. We can go into that. But I want to actually bring up one thing that you mentioned. You can have at the end of your life a head full of amyloid, but still have your cognitive functions preserved. Why is that? That's because of this theory called cognitive reserve. And it's phenomenal, meaning that if you can have a strong performing brain, like the neural connections are so strong, then it can withstand the pathology of amyloid. Very rare. But I do like that hypothesis as well.
- [18:51]
Dr. Kelly Casperson
I love it. I think that the gene theory, the discovery of the human genome, all huge advances. I remember where I was sitting on a couch watching the television when they said, we've now mapped out the human genome and we're not going to have any more diseases anymore because we'll just figure out the faulty gene and then we'll just find a drug to swap out that gene. And like, I remember where I was sitting when this happened and I think what it's done is it's given people the permission to sit on their butt and be like, well, you know, I've got the gene, so. And what people don't understand is genes are not destiny. Like what you were talking about earlier is like how your behaviors and your health can turn on and turn off genes and compensate for them. So I want to talk about the APO4E gene. And when you said 98% of dementia is preventable, what would you say to the people who have that gene?
- [19:45]
Dr. Luisa Nicola
Yeah. So when I say 100% penetrant meaning, like, for example, if you've got a genetic mutation on chromosome 4, you're going to get Huntington's disease. This is something you're born with and we can't right now do anything about it. However, there's three genes involved in what we call early onset Alzheimer's disease, early onset dementia, that is amyloid precursor protein pre snellin 1, pre snellin 2. If you do have a mutation in one of these genes, you will get this disease, right? They generally happen in frontotemporal dementia, like Bruce Willis or dementia with Lewy bodies, etc. Then we have they are mutation, genetic mistakes, if you will. Then we've got risk factor genes, whereas if you have these genes, it just raises your risk of getting the disease. And the strongest risk factor for Alzheimer's disease is the apolipoprotein E gene. And they come in three variants. You've got E2, E3, E4, and you get two copies, one from mom, one from dad. I've gotten tested, I'm an APOE 3 3. So APOE 2, if you've got this gene variant, you're very lucky. I'm envious because it seems to be protective against the disease and vascular damage. If you've got APOE 3, it doesn't raise your risk and it also doesn't help you. It's not protective. So you're part of the average and around 70% of the population is APOE 33. Then you've got APOE 4, and that is the one that is responsible for, for increasing your risk of dementia. Because APO lipoprotein E helps with lipid metabolism in the brain. It helps transport cholesterol and fatty acids through the brain. So if it's dysfunctional, then what can we get? You can get what I call atherosclerosis of the brain, the buildup of plaque in the brain. And that's not good because that can lead to stroke and obviously the downregulation of your blood vessels working. Here's what I want to point out. Around 20% of the population is heterozygous, meaning one copy of ApoE4, one copy if you do have the ApoE4 gene, just one copy if you're an E3, E4, if you are a male, it raises your risk by getting the disease by twofold. If you are a female, it raises your risk by fourfold just by being female. If and around 2 to 3% of the population is homozygous, meaning they have two copies of APOE 4. And that raises your risk if you are a male by tenfold and if you are a female by up to 15 fold.
- [22:21]
Dr. Kelly Casperson
But it's not destiny. Don't throw in the towel. People like. And again, it's pretty rare to have to be homozygous. Even people who are homozygous don't always develop dementia.
- [22:33]
Dr. Luisa Nicola
Here's an interesting study, and this was a landmark study done in Nigeria which showed that they have the prevalence of the APOE4 gene is the highest and they've got the lowest population of Alzheimer's disease cases. Why is that? If people are walking around in Nigeria with an E4, E4, E4, E 4 carriers, but they don't get Alzheimer's disease, then we know that this is a disease of epigenetics.
- [22:58]
Dr. Kelly Casperson
I love that. Let's talk about brain metabolism and hormones. First of all, I hate that we call these. I hate that we call these sex hormones. I think they should be called neuroendocrine hormones, but they're made in gonads. And I'm talking about estradiol and testosterone. And we're looking. Lisa Moscone, you all the brain people are looking at what happens 20 years before that awful Tuesday that affects the pathway of dementia in people. And what happens is outliving our ovarian hormones. A layman's term for that is menopause. But that has to do with periods. And we're talking about outliving hormone levels. But people don't understand that our brain has testosterone and estrogen. And testosterone and estrogen help the brain metabolism. Specifically, testosterone helps glial cells, which are the support, you know, the support people for the marathon of the neurons. It helps myelin sheaths and estrogen and testosterone help mitochondria. And what I'm doing is I'm building our thesis here. Take over. Say what you would like to say about hormones and the brain.
- [24:04]
Dr. Luisa Nicola
I've got two things to say. First of all, your brain cells, the primary fuel source for the brain is glucose. We need it. The brain is. Takes 20% of the total calories that you ingest every day. So it's a hungry organ. It takes a lot of brain fuel. We've seen this in neuroimaging studies with Lisa Moscone that during that perimenopause stage, due to the drop in estrogen, we have a reduction in brain glucose metabolism, meaning that your brain just can't uptake glucose into the neuron efficiently. Our brain fuel is reduced by around 20%. And what I think is really interesting as well, is that we know. And I've sent you one of the studies on this. We know that estrogen actually supports tau in the microtubules. And I don't know if you looked deep into this study, but it was actually pretty fascinating because this was the first study to show that. That estrogen blocks an enzyme. And I believe the enzyme is GSK9.3 beta. I believe that's correct. That's an enzyme that actually phosphorylates tau. So if estrogen blocks it protecting the axon, then that's wonderful. We can have an intact microtubules. We can have an intact axon, therefore we can preserve our brain microtubules. But in the event that we don't have any estrogen anymore, then we're at an even increased attack because the brain can then become. The tau can become hyperphosphorylated. So hormones, these neuroendocrine hormones are so incredibly important for Apoe 4 carriers. But for females in general.
- [25:42]
Dr. Kelly Casperson
Yeah. We have data in men specifically that men with the lowest amount of testosterone have higher risk of depression and dementia. So we have that. We have Lisa Moscone's amazing meta analysis looking at all of all available studies. If you start hormones young again, you have to get on this before enough insult happens. Right. Hormones do a better job of preserving function than repairing function. I really want people to understand that. So if there is a prevention of dementia, it is young, Right? Like young menopause, so 40s, 50s, et cetera, or at least young, meaning 10 years hasn't happened yet. We haven't had the brain undergo those metabolic changes where they're experiencing hits that eventually add up to dementia.
- [26:29]
Dr. Luisa Nicola
Yeah, correct. And I think we focus so much, which you would know this, we focus so much on the Women's Health Initiative, which showed that intervening with hormones at 65 years and above synthetic hormones raised your risk of getting dementia. And this comes down to the density, the estrogen receptor density. Right. And we know this obviously from Roberta Brinton's work as well. And so we now have more evidence to show that intervening with hormone replacement therapy during the perimenopause stage, during that window of opportunity is actually going to be better for brain health outcomes due to receptor density.
- [27:08]
Dr. Kelly Casperson
And I want to pick on. Right, so you have less receptors when you're older because they've down. They've down regulated, but. Right. In the perimenopause, early menopause, your brain upregulates receptors, basically looking for any available hormones. And then it's like okay, well, they're not giving me any hormones, I'll downregulate. And that's Moscone's functional MRI image of the receptors actually going up in early menopause.
- [27:32]
Dr. Luisa Nicola
That is correct. And the more you know, and that's what they showed with the Women's Health Initiative too. And they also use synthetic hormones. And I'm not going to even go into the WHI because I know you've done it so many times, but the synthetic hormones wasn't as, as beneficial obviously as bioidentical hormones.
- [27:45]
Dr. Kelly Casperson
In this case, I want to pick on it a little bit more because what the WHI did in their diagnosis of dementia was symptomatic, self reported or family reported. So these weren't actual physician diagnosis of dementia. And in addition, there was no increased death from dementia. And like you said, if you have dementia and dementia is severe, what's usually gonna get you? So there was no increased risk of death. And I think that's still being used against women in the 70 year old plus who want to try hormones for symptoms or bone health and are being told it's gonna make dementia worse. Is like, even with the oral synthetics, we don't have strong data to say that.
- [28:25]
Dr. Luisa Nicola
Yeah. And my standpoint is this, and I think that you have to be Switzerland right now, especially as a brain scientist, because we don't really have the RCTs, which I know that they're on their way. But what I can definitely say is this, for anybody who is sitting in that they're a bit confused about the data. What I can say is anything at this stage that is going to help you and be a supporter to you to do the things that actually do matter to reduce your risk of dementia, would you do that thing? The answer is most likely yes. Especially if you know that this is the only disease that robs you of who you are. This is the only disease that robs you of your brain. You go to sleep with your brain every night. Isn't the whole point of life to know thyself, to know thyself, to have it be ripped away from you? Because let me tell you, I have seen and it's very devastating. You know, I work with patients who have this disease or who are on their way to getting this disease in that pre dementia state. And when they walk in and they go over a two year period from saying hi Louisa to are you my daughter? It becomes personal because it becomes scary. Especially if they've got three kids, a husband, a grandchild, it does become very personal. So I am here saying that if estrogen is going to support this woman, from not having a hot flash at night to having better sleep or being able to just get up and go to the gym, then yes, I think that we have a pretty good understanding that they should be on hormone replacement therapy.
- [29:56]
Dr. Kelly Casperson
And the data is the strongest in the APO4E people, where hormones are probably even more protective or of added benefit in that more rare population than the general population. But I think that also helps speak to this. And I think, think when the Internet breaks itself over this, number one, people always are like, well, observational doesn't matter and blah, blah, blah. It's helpful to know the randomized control trials are coming looking at prevention, because I didn't know that that's like, that's happening.
- [30:26]
Dr. Luisa Nicola
It's coming with the care, at least the Moscone's group.
- [30:30]
Dr. Kelly Casperson
Okay, wonderful. Because that's going to add a lot of validity. And I think the other reason is social media doesn't understand how hormones actually work. Like, once you have a deep understanding of how hormones actually work, you're like, we have a biophysiologic basis to this theory. In addition, and I always think about this from like a public health standpoint, what do you need for a med that people are going to take for prevention? It needs to be cheap, it needs to not have a lot of side effects, and it needs to prevent something that's relatively common so that you're not just giving a bunch of people something that they're never going to get in the first place.
- [31:06]
Dr. Luisa Nicola
Right.
- [31:06]
Dr. Kelly Casperson
And you're like, hormones. When you look at the public health of what a preventative medicine might look like, hormones. Check those boxes. And I think you can take it apart with so many things, mostly by explaining to people, because if you call these sex hormones, you have no idea. They work in the brain, right? Until you're like glial cells, tau proteins, myelin sheaths. I love Brinton's data. Britain's data looked at the human. I believe it was the Humana database. Women who are on hormones had less risk of all neurologic diagnoses looked at, and this included Parkinson's, multiple sclerosis, Lou Gehrig's disease. How much more data do people need? They're waiting for this randomized placebo controlled trial. But I'm like, we have everything else.
- [31:49]
Dr. Luisa Nicola
The benefits obviously far outweigh the risk. What I think is really interesting about all of this is that we have 80% of all autoimmune diseases are female. Now, if you look at the. If you actually look at the pathophysiology of these neurodegenerative diseases, and we can take Ms. As well. For example, I use emgs, and we use nerve conduction studies, you know, to pick up. And we also use MRIs to pick up on Ms. Disease. Right. And what you can see is on an emg, I will say something called slowing of conduction speed or complete conduction block, which is. Which travels along that axon. And so you can actually see the demyelination of this disease. Right, Demyelination. Where else does demyelination occur? Well, Dr. Roberta Brinton, which you and I have spoken about, showed that during the. During this stage, where women have a reduced 20% of brain glucose metabolism, your brain, as I said, is there for survival. Your brain cells are not going to sit there and go dormant. They're not going to sit there and just die. They're going to do whatever they can to survive. So how do they do that? They need adequate fuel. Where do they get this fuel from? Well, they're really smart, okay. These little neurons, cell bodies, they're really smart for survival. They start to break down and what we call catabolize the white matter, okay. The white matter tracts, which is the myelin sheath, because the myelin sheath consists of a certain cell type, which is oligodendrocytes. They're fatty. These are fatty fuels. So then it uses that fuel source to bring in energy into the glucose into the cell and use that as energy. Right. So there's so many things at play here.
- [33:34]
Podcast Host Announcer
Yeah.
- [33:34]
Dr. Kelly Casperson
And I think, again, people's lack of understanding of how the body actually works hurts them because it's like, well, muscles will. Will break down for food sources. The bone breaks. We take bone for food sources. Like, we use the brain and the fatty acids for food sources, if needed. If needed.
- [33:53]
Dr. Luisa Nicola
Well, this is what happens when we actually produce ketones.
- [33:56]
Dr. Kelly Casperson
And I don't want anybody to think that we're forgetting lifting weights, exercise, not drinking, not smoking, controlling blood glucose, not eating too much sugar, like all of this plays into brain health. But I think given your expertise and my expertise on hormones, we really want to explain hormones to people.
- [34:14]
Dr. Luisa Nicola
Yeah. And can I just say quite transparently, one of my first ever systematic reviews was actually on resistance training and mild cognitive impairment. Now, I'll be damned if I. If somebody tells me that there is a better intervention for delaying the onset of these neurodegenerative diseases than resistance training. Where we go with hormones is hormones can help you, support you, to lift heavier, to motivate you to get to the gym. We've also completely misunderstood certain molecules like dopamine. You know, you mentioned earlier that testosterone is a motivation hormone. Then we think about, everyone thinks that we've denoted what dopamine is. It's a movement molecule.
- [34:58]
Podcast Host Announcer
Yes.
- [34:58]
Dr. Luisa Nicola
Responsible for reward. Yes. Responsible for motivation and drive. But hello, what is Parkinson's disease? You know, so there's a lot of, like, unknowns happening in the social media sphere.
- [35:10]
Dr. Kelly Casperson
Yeah, no, I think, you know, social media builds on people's fear. It builds on people's current lack of understanding of how the body works. It builds upon people's desire for a magic bullet that fixes everything.
- [35:25]
Dr. Luisa Nicola
Right.
- [35:25]
Dr. Kelly Casperson
And so there's so many stance. Why I love podcasts so much, because it's like you actually can get into it and explain your stance. Because when I ask a question on a clip on social media and I say, does the brain eat itself, which is the layperson's term for breaking things down, or catabolism, the opposite of anabolism. And the body does both. It builds and it tears down. That's how living organisms work. The Internet literally poops its pants because it can't handle that question.
- [35:55]
Dr. Luisa Nicola
Because it's confronting. Right. We just got stuck on. I won't take up too much of people's time, but I do want to say that there is hope, because I mentioned to you earlier, you've got this head full of amyloid when the brain is trying to protect itself. Well, guess what, guys? The brain's really smart. During deep slow wave sleep, what happens? The glial cells actually shrink. And this is an evolutionary process. So your cerebral spinal fluid is. Can wash out through the brain and exit the brain and taking with it all of the debris and all of the amyloid beta.
- [36:27]
Dr. Kelly Casperson
The self cleaning oven phase of your day.
- [36:30]
Dr. Luisa Nicola
Yes, but glymph comes from the glial cells actually shrinking and, and exiting all of that. But here's the thing. What is the number one vasomotor symptom for menopausal women?
- [36:43]
Dr. Kelly Casperson
Hot flashes. And nice.
- [36:44]
Dr. Luisa Nicola
What? Vega. So what is keeping us from getting out of. What is keeping us from deep sleep?
- [36:50]
Dr. Kelly Casperson
Hot flashes. And night sweats.
- [36:51]
Dr. Luisa Nicola
Hot flashes. There we go. So ergo, the supporter hormone estrogen, progesterone. If we are, if we have this available to us, maybe we don't get night sweats, maybe we don't get hot flashes, and then maybe we sleep through the night. Just one night of sleep deprivation can raise Your circulating amyloid beta levels. Just one night of sleep deprivation.
- [37:15]
Podcast Host Announcer
Yeah.
- [37:16]
Dr. Kelly Casperson
As a surgeon who went through surgeon training, that's frightening. And having babies, the body's ability to repair itself when given proper care is my. The way I sleep at night, because I'm like, lord knows, the brain took some hits in the 20s and early 30s.
- [37:33]
Dr. Luisa Nicola
Correct. And if you don't sleep at night, you're less likely to get up in the morning and go to the gym and lift heavy.
- [37:40]
Dr. Kelly Casperson
You're more likely to eat sugar.
- [37:42]
Dr. Luisa Nicola
Yeah. Leptin, ghrelin are all out of place. And we forget that lifting heavy guys is not just about aesthetics. You don't lift with your bicep, you lift with your brain. And you're not just doing that. You're also supporting something called cerebral angiogenesis. So you're actually growing new blood vessels. On the outside. On the outside, but on the cortex of the brain, which is feeding your brain cells with nutrients and oxygen.
- [38:09]
Dr. Kelly Casperson
Blood flow. Blood flow, Blood flow. I mean, that's what's so interesting about the Viagra and the PDE5 inhibitors is it looks like. And again, there is no randomized placebo controlled trial on this, but it looks as if people who take that, which one would argue they have a higher risk of cardiovascular disease and that's why they're taking these medications, which is a dementia risk factor, but they actually have less risk of dementia. Why it's a blood flow drug. Very interesting. In our time left, I want to talk about two things. Number one, there is more and more data looking at the prevention of dementia in people who've had Shame Pringles vaccines as adults. How does this vaccine seem to protect the brain?
- [38:44]
Dr. Luisa Nicola
Yeah. And this is huge. And for some reason, God knows why, it's a controversial topic. I think it's because it overlaps with the COVID vaccine. So I want everyone to know that this is not about vaccines as a whole. So when we get chickenpox as a kid. And by the way, I've never had it, I had to ask my mum, she's like, I don't think you did.
- [39:02]
Dr. Kelly Casperson
Oh, I had raging chickenpox.
- [39:05]
Dr. Luisa Nicola
I never had it, according to my mother. So. Who also doesn't know her age of menopause, which is interesting. So I'm like, you're not helping me at all. So when we get chickenpox, chickenpox actually stays in the system and it lies dormant in the dorsal root ganglia of the spinal cord. We don't need to go into what that is, but it lies Dormant, asleep in the spinal cord and the reactivation of that. So when these little pathogens wake up, when this virus wakes up under times of stress and low immunity, it reactivates and it comes back. But not as chickenpox as shingles. And people think that shingles are. It follows the dermatome of the nerve root. But people think that shingles is just this awful, painful rash. But what it's also doing, hey, think spinal cord. What happens when it's in the spinal cord? Well, it goes up and it goes into the brain. It's already in the central nervous system. And in the brain it causes neural inflammation and it causes the breakdown of our neurons. So shingles is increasing our risk of getting dementia. Now we've got three beautiful studies, really well done, natural experiments both in Wales and in Australia that showed that just getting the shingles vaccine over the age of 50 can decrease your risk of all cause dementia and Alzheimer's disease by up to 30%.
- [40:28]
Dr. Kelly Casperson
Neuroinflammation is bad. Preventing neuroinflammation is protective, correct?
- [40:33]
Dr. Luisa Nicola
Yeah. I made my parents, my parents have had the shingles vaccine more than once. They are. And it seems, look, it seems to be more protective if you're over the age of 50. And like, where do we get the most stress?
- [40:45]
Dr. Kelly Casperson
Yeah, yeah. A hit at a certain age is more of an insult than a hit when you're 21 years old. I'm using like very like sport analogies right now.
- [40:55]
Dr. Luisa Nicola
And so again, would you do whatever you could if your mother stopped remembering your name? Would you do anything you could have done to prevent that?
- [41:03]
Dr. Kelly Casperson
Well, we gotta talk about that for a hot second because people don't know. I posted this on Instagram a while ago. There are two randomized placebo controlled trials and these are old studies because we studied hormones before the whi, so it's old studies. And it was placebo patch versus estradiol patch in women with mild cognitive dysfunction. It wasn't like really, really bad dementia, but it was, it was early, they had a diagnosis like shit was going down, right? And there were, I think six month studies. And the women on the estrogen patches had cognitive improvements compared to placebo, which did not. Now, this didn't cure things, right? But it made things better, dare I say, slow the progression, right? And so when people look and they're like, oh, it's, you know, all is lost is like as much as you can have your loved one exercise, as much as you can decrease insults like alcohol, as much as you can have them have regular sleep patterns. And there are two studies looking at this. And what's so embarrassing about all of it is here we are trying to prevent dementia or cure it when we have it. And we've thrown billions of dollars at the amyloid hypothesis and gone nowhere with those medications. And we've got two small studies with significant signals and we don't even know they exist. That is an embarrassment to natural hormones and trying to help. Again, not a rare disease. People.
- [42:28]
Dr. Luisa Nicola
160 million people worldwide will have this disease by the year 2050.
- [42:33]
Dr. Kelly Casperson
Yeah, if only, if only that they got better because they're probably sleeping better. But I just want people to know these papers exist. And it admonished the research world of like, why aren't we looking more into this? Because prevention is fantastic. But some people already have the diagnosis and they want to know what can we do on wrapping up. Let's talk about creatine and why you like creatine.
- [42:58]
Dr. Luisa Nicola
So creatine is the most widely studied supplement in the world and arguably the safest. And we naturally produce creatine every day, but we're only really producing around 2 to 3 grams of it. So we have to supplement with it. Why? Because it helps us cell energy metabolism, something that is depleted. The reason why I love it so much, we've just had a pilot study on patients with clinically diagnosed Alzheimer's disease where they were supplementing with 20 grams of creatine per day over an eight week period, which improved their cognitive functions. And when you actually look at this study and think, how is that even possible? That is because the widely studied notion of taking 5 grams of creatine per day, we know now that that just saturates the muscle. You know, your muscle takes 5 grams of creatine, you've saturated the muscle. So now we have to have excess creatine outside of that so it can cross the blood brain barrier, get into the brain and help the brain work better. So I love creatine because it actually works best in the background of stress. So if you've been sleep deprived, take 10 grams of creatine and you'll feel better. If you are, if you want to go to the gym, you want to lift harder, perform better, take creatine. We used to think it was five grams a day, but now to get the brain boosting benefits of it, you want to take around 10 to 15 grams a day. And I will add this and I'll send this to you. A study just came out in the last two weeks that showed creatine's anti cancer effects. So I'm about to break the Internet with that one.
- [44:33]
Dr. Kelly Casperson
They get your creatine from a reputable source because gummy creatine gummies on Amazon don't always have creatine in them.
- [44:40]
Dr. Luisa Nicola
Yeah, there is differences in manufacturing of the creatine.
- [44:43]
Carvana Ad Narrator
Super important.
- [44:44]
Dr. Kelly Casperson
All right, my love. Thank you for coming, everybody.
- [44:46]
Podcast Host Announcer
Check her out.
- [44:47]
Dr. Kelly Casperson
Her Instagram's phenomenal, her podcast is phenomenal, and she's also a phenomenal friend. So I'm feeling pretty happy over here. Me too.
- [44:56]
Dr. Luisa Nicola
Thank you, Dr. Kelly Kasperson. You are my mentor and I learned so much from you, and I'm so happy that you exist in the world. And I'm so happy that Jane Fonda fell in love with your hair just as much as I did.
- [45:07]
Dr. Kelly Casperson
Oh, let's hold on. Okay, we'll wrap up with sharing this one thing because it's not on the social medias yet. I was on a panel with Jane Fonda in la and she said that my hair looks like it's having an orgasm,
- [45:19]
Dr. Luisa Nicola
which I think is. I. I didn't even think about that. How did she think about it? And she's 88.
- [45:24]
Dr. Kelly Casperson
I never thought about it. That woman's got a brain and she exercises. God bless. Well, hopefully that conference will give me that clip because everybody knows how amazing Jane Fonda is. And now I'm like. And wait, there's more.
- [45:37]
Dr. Luisa Nicola
Yeah. All right.
- [45:38]
Dr. Kelly Casperson
Much love. Thank you for helping.
- [45:39]
Dr. Luisa Nicola
Well, thank you for having me.
- [45:41]
Podcast Host Announcer
If you found this episode funny, helpful, insightful, please take a moment to follow rate and share the youe Are Not Broken podcast with someone who might need this conversation too. That support is how this information reaches more people. And thank you. For courses, books and my monthly membership and the Casperson clinic information, visit KellyCaspersonMD.com this podcast and all content from Dr. Kelly Casperson is intended for educational and informational purposes only, and this is not a substitute for individual medical coaching or psychological advice, diagnosis or treatment. Always seek the guidance of your qualified healthcare professional with any questions you may have regarding your health. Never disregard or delay medical advice because of something you've heard on this or other podcasts. Thanks for being here. And remember, you are not broken.