Ketosis and Alzheimer's: A Metabolic Neuroscience Journey With Dr. Stephen Cunnane

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies, such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only and we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

Welcome back to Metabolic Mind, a nonprofit initiative of Baszucki Group where we’re focusing on the intersection of metabolic health and mental health and metabolic therapies, like ketogenic therapies for mental illness. I’m your host, Dr. Bret Scher.

Today, we’re going to continue our discussion on metabolic therapies, ketogenic therapies for neurodegenerative diseases, such as Alzheimer’s disease. We’re fortunate enough to be joined by Dr. Stephen Cunnane. Dr. Cunnane is a professor in the Department of Medicine at the University of Sherbrook, and he’s also the Chair in Keto Therapeutics, which is a recently new position and very exciting, which we’re going to hear him talk about.

He’s published over 350 articles in peer reviewed journals. He’s been the author on five different books, and he’s a researcher in the Center of Aging. And Dr. Cunnane and it’s really interesting because he truly is a pioneer in this field and stumbled upon it by accident. So, we hear about his origin story, what got him interested in studying ketones, in the brain.

And then how that sort of transition to ketones, ketogenic therapy for neurodegenerative diseases. And since he’s been there in the beginning and he’s still there now, he can give us sort of the perspective on how the field has changed, but in two different ways. How the research field has changed, and then maybe how the clinical field hasn’t changed nearly as quickly and has been very slow to adopt and why that is, what he thinks needs to change.

Plus, we hear about some exciting new projects he’s working on. I think this is a really interesting exploration of Stephen and his journey through this, and what it means for the field of keto therapeutics. So, I hope you enjoy this interview with Dr. Stephen Cunnane.

Well, Dr. Cunnane, I’d love to start by hearing what got you interested in exploring ketones as a potential treatment for neurodegenerative diseases. Because this is a huge field with lots of research going on, but when you look back over the past 10, 20 years, probably not so much about ketones.

It’s definitely an alternative approach. So, what got you interested in that alternative approach? 

Stephen: 
I guess there’s two parts to the answer, Bret. One is serendipity. And the other was that I’d heard, roughly at the same time that I made the serendipitous observation in a research project, which I’ll come to in a sec.

I heard about the ketogenic diet in the film, First Do No Harm, which was the first widely publicized way of seeing the treatment of epilepsy with the ketogenic diet and with Meryl Streep and so on. And I thought that was the craziest thing I’d ever heard about. Because like most people in the early nineties, and perhaps many people today, I thought low-fat was important, and the high fat was going to sort of kill people and all the rest of it.

Pretty naive view, but that’s where my I was at. And so, to be honest, there weren’t that many people working on even on the ketogenic diet in epilepsy in the early nineties. The serendipitous observation that really made me pay more attention to the ketogenic diet in epilepsy, was that we, by mistake, discovered that polyunsaturated fatty acids that are in our diet, like alpha linoleic acid and linoleic acid, are actually moderately ketogenic.

And more interesting than that, during early development, at least in the animal model we were studying, they were quite important sources of carbon to help build the lipids in the brain, which completely blew me away. I was working on omega-3 fatty acids and the uptake of DHA into the brain.

And here I was seeing one of the precursors of DHA that was being incorporated into cholesterol and saturated fatty acids in the brain at about 10 to 20 times the amount that was going into DHA. It seemed completely implausible. And then I learned that the ketones were underlying that process that they, the fatty acids, are broken down by beta oxidation.

And some of the carbon is lost to carbon dioxide, but some is recaptured and used in lipid synthesis. And so, this got me interested in brain development, and neurodegenerative diseases came along in my career at least 10 years later. But it was the early development thing that struck me.

And some of the pioneers in the 1960s that were looking at ketones and early brain development have all been forgotten about now. But that’s, in fact to me, what started this whole thing was that if ketones are important for early brain development, maybe that explains, in part, why they’re beneficial in childhood epilepsy.

And when I got the opportunity to move to Sherbrooke, because at the time I was in Toronto, I had the opportunity to start doing brain imaging. And the PET imaging that we started here was something they were quite prepared to try and make the ketone tracer. And to me, that was really an important step forward to look inside this black box and see what was going on.

We still didn’t have Alzheimer’s disease on the radar at the time, but there was no opportunity to study ketones in early development for me. And since I was affiliated with the Research Center on Aging, I said, if they’re important for brain development, perhaps they’re important for brain function as we age?

And maybe there’s something we can learn about the way the brain is using these two fuels that would be relevant to healthy brain aging? And it’s turned out to be very interesting. But at the beginning, we had no idea where this was going to take us. 

Bret: 
Yeah, really interesting.

That started with just the scientific curiosity of ketones in the brains and the interaction. And I like that you mentioned imaging, though, because like you said, the brain’s a black box. How do we know what fuel the brain is using? How can we tell if it’s using glucose or ketones? So, you had to help develop this technology to differentiate that.

So, give us the one minute layman’s version of how can you tell what the brain cells, the neurons, are using for fuel to create energy? 

Stephen: 
So, imaging, PET imaging specifically, positron emission tomography, you can follow different isotopes, different molecules as they’re being used by the brain.

What you get is an image of the activity of the utilization of those molecules in different parts of the brain. And what we’ve known since the 1980s, since the dawn of PET imaging in human studies, is that glucose is the main fuel that was known already. But you can see the pattern, and you can see that the gray matter using twice as much glucose as the white matter, for instance. But the white matter is not inert.

It’s not just an insulated wire. It’s actually actively metabolizing, making myelin, making the insulation for the nerves. And there’s an active processes involved there. Now, we also know that ketones are used by the brain. We’ve known in that since the sixties with George Cahill, for instance. And that during starvation, ketones become a dominant fuel.

But little was known about the process in relation to aging. And the big surprise for us was that we knew that there was this problem when getting glucose into the parietal cortex in Alzheimer’s disease. That had been known since the eighties as well. Even on the crudest PET images that were available 40 years ago, you can still see that area of the brain is simply not metabolizing glucose very well.

And the interpretation always was that those cells are dying or have died. And hence, they’re not going to use much fuel, of course, because a dying cell doesn’t have any energy requirements. So, it was interpreted as a consequence of the disease, and we said, two points. One is that problem seems to be present, the metabolic problem seems to be present, before people are clinically diagnosed with Alzheimer’s disease.

So, maybe it’s not just a consequence? But there are two fuels anyway, and under the right circumstances, the brain is quite happy to use ketones. And lo and behold, when you look at the image for FDG and for ketones, you don’t see any deficit in ketone utilization in the parietal cortex at all.

Observation that was novel at the time, it’s confirmed by four different techniques now in in labs around the world. So I’m quite confident it’s a very robust observation. 

Bret: 
Yeah, so just a quick summary. So, FDG meaning the glucose uptake. So, in these cells, glucose uptake goes down, but ketone uptake does not. They can still use ketones for fuel.

Therefore, they’re not dead cells, like you were saying, because they’re still using energy. They’re just using ketones. 

Stephen: 
They probably will be in the course of the next couple of years to come, if they’re starving. And if you give them the right fuel, they can use it. So, the question then is how do you preserve them, keep them alive and keep their communications alive so that they can keep the brain function alive, the memory and the executive function and language and these cognitive parameters that decline in Alzheimer’s disease?

But that PET imaging gives you a window on that process, and it shows you where the problem is. If you’ve just had a stroke, it’s probably going to show you that area of the brain has gotten, anatomically is different, but also has a problem with the glucose uptake. But it also, if you do it correctly, it can show you the magnitude of the problem.

How much glucose is missing? Is it 2% of what the brain would normally want to see, or is it more like 25%, which is the case in Alzheimer’s disease? It’s a huge number. It’s like trying to run an eight cylinder car on five cylinders or six cylinders. That’s old technology when you think of today about being ecologically more responsible for electric cars and so on.

But, the analogy is that, in fact, the brain is a hybrid car. What we’re getting it to do is to run on the electricity and the battery and the electrical motor, and bypass problems with the gasoline engine, which is what’s happening with the glucose. 

Bret: 
Yeah, it’s so interesting that the terminology is frequently that ketones are an alternative fuel for the brain, and I always thought that’s so interesting that it’s alternative.

It’s only alternative, basically, because we’ve made it alternative through our lifestyle. But when you see the way ketones are used, would you say it’s a primary fuel or a preferred fuel, or it runs better? Can you use, I don’t know, I say like judgmental terms like that to say that the brain is meant to run on ketones more than glucose, perhaps?

Stephen: 
In the infant, there’s not enough glucose getting to the brain to meet the infant’s brain energy requirements when it’s born. So, they’re an essential fuel for about 25%. Ketones are supplying about 25% of the energy requirements of the newborn infant. So, they’re essential for that purpose.

Bret: 
Essential, meaning you cannot survive without it. 

Stephen: 
That’s right. And the fact that we’re born with fat babies, our species, if they’re born at term, if they’re born normal and healthy, they’ve got fat. They’ve got 5 to 600 grams of fat, and that is helping to generate the ketones to meet their brain’s energy requirements.

So, it’s essential. Now, it’s still not the main fuel in the neonate. And then, and if that baby’s being breastfed, then that’s the ideal situation. So, now we progress towards adolescence and adulthood, and we’re on a typical western diet, whatever that means. And obviously, it’s predominantly carb. And the ketone contribution goes down to around 3 to 5%.

The only way you can get it back up is to really suppress carbohydrate intake. And when, if you’re on a ketogenic diet, which is as you know well, it’s probably under 5% carbohydrates in the diet. Ketones will be supplying on the order of 40 plus percent of the brain’s energy requirements.

Still not the majority. But what’s very interesting is that when you are on a ketogenic diet and you have no problem with brain glucose or ketone utilization, such as in a young, healthy adult, for instance, glucose uptake will be suppressed when the ketones are available. So ,when you provide ketones, they are, in fact, the preferred fuel.

It’s a term that I know, rubs some people the wrong way, but I think it’s the correct term. That ketones, when they’re available, and both fuels are available and there’s no limit to utilizing both of them, ketones will go in and will suppress utilization of glucose. And that’s been shown by two different techniques.

Totally different techniques as well. So, I think that’s a robust observation. But for the majority of people, unless you’re on a very strict ketogenic diet, glucose will still be the main fuel. And I think that’s normal, and that’s okay. But underlying your question is, are ketones doing something that glucose cannot do?

Are they complimenting in some important way? And that’s something we still don’t know. But when you’re born, they are actually the main fuel to make, not the main fuel, but the main substrate to make brain lipids. Cholesterol is quite an important component of the brain. Saturated fats are very important in the brain to make the myelin, but also in the gray matter? And so, they are the dominant source of carbon when you’re born to make the brain lipids.

Bret: 
Yeah, so interesting to think about how it is from birth throughout and then changes throughout life. But then again diseases of aging, like Alzheimer’s disease, neurocognitive diseases, that it becomes important again. And so let’s fast forward then to when your research turned towards Alzheimer’s disease, where so much of the focus has been on the amyloid plaques and the neurofibrillary tangles. And that’s been the predominant focus for decades and decades.

And here you come and say, why don’t we start looking at energy utilization and change energy utilization? Did that seem just completely revolutionary at the time and completely crazy to some neurologists and researchers at the time? 

Stephen: 
We’ve always had trouble convincing the neurologist that it was relevant because they’re all looking for the magic bullet treatment to these sorts of disorders.

And the amyloid seemed to be the obvious choice. It’s present not in all people with Alzheimer’s disease, as you may know. So, it’s not a guarantee that having high amyloid may, in fact, be associated with Alzheimer’s but it may not. And you can have, Alzheimer’s disease clinically without a large amyloid load.

But so yes, it’s always been the orphan approach to Alzheimer’s therapeutics. But we came to it honestly in the sense that we were never intending to treat Alzheimer’s disease. We were simply looking at the metabolic state of the brain in a healthy, older person. In fact, we spent a lot of time trying to define what is a healthy older, how do we define a healthy aging?

Anyway, and what is the state, the energy state, of the brain in that the person that we’ve defined as cognitive healthy. And we ended up defining it based on cognitive norms for normal cognitive performance at certain ages. And we always found that there was a 5, around 5 to 7% lower glucose uptake in the brain, and even in the healthiest elderly people that we could identify.

And we said, what’s happening in mild cognitive impairment, which is the early stage of Alzheimer’s disease and Alzheimer’s disease, and there’s a gradual progression towards a lowering of glucose uptake with a steady uptake of ketones. So we said, wow, that’s interesting. If the cells are not dead and they’re able to metabolize ketones, maybe this can help support brain function?

So, what are we going to give people to supply them with more ketones? This is around 2012 or so. I knew about the ketogenic diet, of course, at this point, and I was doubtful the ethics committee was going to let me put 75-year-olds on a ketogenic diet for six months. And even if they were going to permit me to do it, I knew enough about Alzheimer’s disease at that point to realize that they’re a fragile population.

And it’s maybe capricious sounds like a little, maybe not fair, but they’re likely to change their mind. And they might say, oh yeah, I’m willing to do this project. But a week later, they might change their mind. So, we need something that’s more likely to take over an extended period of time.

And we ended up settling on MCT, medium chain triglyceride, as a supplement knowing that once you give the dose, you’re going to get a rise in blood levels, and it’s going to go down. And if you get another dose later on, it’ll rise and go down. So, you’re making a compromise. Either way, they’re on a ketogenic diet for two weeks. It’s not enough to learn anything about their cognitive function really. If they’re on MCT for six months, that’s long enough. But you might not have high enough ketones to change anything in their lives.

So, that’s the gamble we took. And we came out ahead in the sense that, in looking at mild cognitive impairment, we actually showed you could improve cognitive performance in all the five cognitive domains in the very early stage of Alzheimer’s disease where there’s only a mild deficit to start with.

Bret: 
Yeah, so this was fascinating. It was a six month randomized controlled trial that you did with the MCT supplement versus a placebo supplement. And as you mentioned, there was improved cognitive function for memory, executive function, language. And one important thing when you’re dealing with trials is, what is the magnitude of improvement?

Was it just a tiny improvement? Was it clinically relevant improvement? So, how would you summarize the degree of improvement that the people on the MCT supplement saw in six months? 

Stephen: 
So, the main improvement that we saw, in terms of magnitude, was in language. And it was borderline clinically relevant.

So, the other changes were also statistically important. They’re considered to have a decent effect size, a moderate effect size, which is a proxy for clinical utility. But remember in mild cognitive impairment, they’re fully autonomous in their daily lives. They’re able to get around to drive, remember their PIN number for their bank account and so on.

So, they’re only starting with a very small deficit that you can define on these objective tests. So, you’re not expecting a dramatic change in their lives that you can see. And when they walk into the research center, which you do see occasionally with the ketogenic diet as a colleague of mine, Russell Swerdlow, in Kansas City has said, I could tell in a couple of my patients that were on the ketogenic diet when they crossed the parking lot to come into the research center.

I could tell how much better they were doing. So, that jumps out at you because the ketone levels are a lot higher on a ketogenic diet than they will be on a ketogenic supplement. So again, it’s often a practical question, and you’d like to get ketones up to a certain number. But what’s the way to do it?

And what’s the chances of sustaining someone on that treatment for an extended period of time? What’s your placebo going to be? And work with the ketogenic diet, but also with the ketogenic supplements, faces this sort of scrutiny that, okay, you’ve seen in effect. What was the control group on?

And for the ketogenic diet, that’s a tough call to set up a controlled study. We were able to use a control group with the MCT. It’s a question of progressing towards solving these sort of practical issues that make it credible in the end. And so far, it’s been promising.

Bret: 
Yeah, and other researchers in this space, we recently interviewed Dr. Matthew Phillips, who also did a study on ketogenic intervention for Alzheimer’s disease, and showed improvement. So, it’s clear that the needle is moving that direction, which I think for you must be fascinating to think about when you started in this field, how nascent it really was.

And now, to the point where there are a number of different intervention studies that keep getting, I guess you could say, better or keep adding to the literature and hopefully progressing. And now to the point where there’s even a Chair in Keto Therapeutics, which is what you are in your new position.

So would you ever have dreamed that it would’ve progressed this much and this quickly? Some people could say it’s been slow, but by research standard, I would say it’s been fairly quickly. So, I don’t know. Would you ever have dreamed it would’ve happened? 

Stephen: 
Oh, you feel both ways about it.

You watch the time go by and the years go by, and you say, no one seems to be doing this any faster than we are, in terms of getting clinical results published that are randomized controlled trials. So in that sense, I feel good. But in the end, you spent 30 years working on this, and you’d like to see it go faster and to be more accepted.

Because there’s, I think, there’s a certain resistance, if I could use that word in the medical establishment. By and large, the expectation is that drugs will be the solution to many of these diseases, whether it’s diabetes, hypertension, mental health. In fact, and they’re the mainstay, for better or for worse. They’re there, and they’re in your face.

And so, the idea for a neurologist to see, or a psychiatrist or a geriatrician, to see the disease through the lens of a metabolic problem and to reconfigure the way they think about the disease. I think that’s probably the main challenge ahead now, is to get an acceptance that there is a metabolic foundation to many of these disorders, and there’s a metabolic solution.

It doesn’t necessarily involve drugs and their side effects, but if you come back to the original disease that was treated with the ketogenic diet, that was epilepsy. And every generation, new generation of epileptic drug that was developed, set back the ketogenic treatments by another decade or so.

But the side effects were often worse than the benefits. And yet, there’s so many people were frustrated. The Baszucki family has went through a period of immense frustration when they realized that there was a different approach to their son’s mental health issue.

It’s exactly the same story with in epilepsy with Jim Abrahams back in the nineties, which got him to produce the film, First Do No Harm. Why is there a cultural resistance or a cultural obstacle in the medical establishment? And that’s something that we have to learn to deal with and try to solve.

Bret: 
Yeah, it’s very well said. And if you can imagine the two different graphs, one of the progression of research in these fields, and one is the adoption in clinical practice and with epilepsy. The research took off, and there are dozens of randomized controlled trials and Cochrane reviews on ketogenic therapy for epilepsy.

But the clinical uptake was so slow compared to the research, and I think we’re probably seeing something similar with ketogenic therapy for neurodegenerative diseases that we see more pockets of people doing research, but the clinical adoption is still very low because of this drug centric-approach that you mentioned. 

Stephen: 
I think Ancel Keys casts long shadow over the ketogenic therapies in the sense that fat is the enemy. And if there’s more fat in your diet, we’re still, as a worldwide, we’re still very much affected by that dogma that fat is the enemy. And that’s something that we have to reconfigure. And our older population on the Alzheimer’s study, they were really concerned that MCT is a saturated fat.

That’s going to be bad for me. I’m going to gain weight. So, I said, these are the results, and the result is that you don’t gain weight. And so, it’s one study at a time, gradually. But we have, society has seen fat is the enemy for the past 50, 60 years, and it’s not going to change overnight.

Bret: 
Yeah, I want to go back to something you said where you said you doubted that the IRB and the ethics committee would allow you to put 75-year-olds on a ketogenic diet, implying that they would assume it is a dangerous diet and they should not go on it, which is of course, backwards thinking. Do you think that’s changed?

Do you think if you went to an IRB tomorrow that it would be, they’d be much more accepting of it? 

Stephen: 
Yes, I think it has changed. it’s changed because of results of people. People like, Virta Health, and the acceptance now that type II diabetes can be treated and can even be put into remission.

And the openness, I think, that the American Dietetic and Diabetic Associations have to a lower carb intake is coming. So, I don’t know whether the cardiologists have turned the page on that yet. That’s something you might know better, but I don’t think the neurologists have yet.

So, there’s still a fairly strict view of treatment options. And to be fair, if I was a neurologist, I would have a list of options that I’d be allowed to use that my association has approved, and the ketogenic diet is nowhere on that list. What risk is that person taking to be ostracized or to even be disciplined for introducing a treatment that is not accepted?

If it’s not accepted, it’s probably because it doesn’t work. That’s the logic. And so, we need to change that. And it’s still going to take time. 

Bret: 
Yeah, and of course, if the alternative is just to let them continue to eat their standard American standard, industrialized diet, nobody thinks twice about that.

But to put them on a ketogenic diet would be potentially risky or dangerous from a medical perspective, which doesn’t quite fit, does it, that framework? 

Stephen: 
No, and the evidence is there, that it is acceptable, because often they said it might be effective, the ketogenic diet, but people won’t tolerate it.

And even if they tolerate it, it’s too expensive or it’s limiting in its vitamins. And there’s always this search for some other reason to not try it. When, in fact, those reasons aren’t valid, but we have this sort of internal psychological resistance that it’s pretty hard to overcome. 

Bret: 
Yeah, and when you hear these personal stories of how much people have improved with ketosis, that all of a sudden it becomes the most sustainable and easiest thing to comply with because of the benefits you’re seeing. You don’t want to see disappear. So. Many people would do anything they can to stick with it with that type of benefit.

And yeah, it’s anybody who says that clearly hasn’t tried it or doesn’t know enough about it to realize that it can be incredibly sustainable and easy for many people. But our society is not one that promotes it, and our society is one that makes it more challenging. So, I guess, it’s understandable some of these hurdles.

So you have to figure out how do you change things from a research perspective so that we can get some infiltration into the clinical perspective. So, when you think about that and you think about connecting the dots, where do you think research has to go to make it more clinically acceptable?

Stephen: 
Oh, we need more robust results. My RCT had 40 people per group. That’s borderline significant in terms of the sample size. But most neurologists will say it’s going to take you 300 people per group, normally to be convincing. Of course, we didn’t have access to $5 million to do it with 300 people.

But more robust studies are needed. Placebo is an absolutely essential part of this process where you’re working with a supplement. It’s basically impossible to do with a ketogenic diet. I don’t know whether we’ll ever have the robust results with the ketogenic diet in older, in neurodegenerative disorders.

I think the thing that sort of resets the table a little bit is the internet. And the families and patients are able to access the information and judge it for themselves and either push their doctors to agree or to say, that I’m going to do it despite your misgivings sort of thing.

There are companies making money off ketogenic products. A lot of money in some cases. And I think there’s a question of social responsibility to produce a placebo so the research can go forward. To engage some percentage of their profits in research, that can be independently vetted by some sort of scientific advisory board, and to make this treatment more credible.

Because at the moment, it looks like the wild west out there, and it’s only feeding the concern that some clinicians will have that this is simply profiteering, and there’s nothing really scientifically valid underneath this. And so, I think the companies are going to burn, they’re burning the candle at both ends.

And at some point, they’re missing the opportunity to be more responsible and to have longer term view of the profits they could make because it’s a more credible treatment for serious chronic diseases.

Bret: 
Yeah, that’s a great point. As we know from medicine, that anytime industry and profits get intertwined with medicine, it becomes quite complicated. And you never know what to trust and what to believe when profits get in the way. Which is one thing that’s so great about a diet when we’re talking about food.

If we’re not talking about products and we’re just talking about eating a certain way, nobody is going to have a patent on that. And the focus is more on helping people improve than really helping the bottom line. So hopefully, that purity can help people understand these results better than industry-sponsored results.

But maybe that’s naive? I don’t know.

Stephen: 
It’s a challenging process. If you need to stop, not need to, anyone who smokes needs to stop smoking. But smoking is not something you need to do, except because of the addiction. It’s not, you don’t need it for, it’s not life giving. It’s life sapping. Alcohol is not something you need.

Food is something you need. So, people will have to make choices. And they may prefer at some point to have eaten more sugar in their diets or more dessert or more pop or whatever it is. And they have to learn to consume less, and consume differently. And that’s a psychological, and an appetite to adaptation that is is slow.

In an older population, it’s not easy to get that commitment, that motivation. How does a 75-year-old in a residence where everyone’s getting dessert twice a day, decide not to eat dessert, for instance, as a start to reduce their carb intake without changing whether they eat corn flakes, without changing whether they eat rice or potatoes? Just trying to reduce their desserts, for instance?

It’s a challenging process. I’m doing it in a residence right now. We started with a 10-day project, and we got some very encouraging results. And we’re going onto a two-month project now, but there’s a lot of resistance. I don’t want to have to eat this. I’m finally at a stage in my life where people are taking care of me.

I can afford to be in this nice residence. Why? Why would I change what I’m going to eat? You’re taking medication for diabetes. Wouldn’t you like to stop that? Some don’t. I’m sure people with mental health issues, it’s the same problem. How do you motivate them to make that change when perhaps the only pleasure they’re getting out of the day is the bag of chips or two donuts or whatever it is?

So, there’s quite a challenge. And I’m by no means, I’m not a behavioral psychologist, so I’m not sure the best way to approach these issues. But one approach is with the ketogenic supplements, which allows people to eat what they’re eating. Ideally, they would change towards a lower carb, but they can still get the ketones because the ketone production from medium chain triglyceride, or from a ketone salt for that matter, is independent of insulin.

Whereas, if you’re depending on the body to make the ketones without the supplement, you have to get insulin down. So, you have to get that motivation level to reduce your carbs and so on. So, there are different strategies, and they’re not mutually exclusive. They can be combined, and that’s what we’re starting.

In the trial in the residents this fall, is a combination of MCT plus a 50% reduction in carb intake. 

Bret: 
Oh, that’s wonderful. I think we need programs like that, especially in a controlled setting like that, like in a residence, that can really control what people are eating and really see the impact. Because like you said, when you’re getting dessert twice a day and every meal is high carb, and that’s just the way it is. You don’t question it.

And so it takes someone like you to come along, and question it and change it. And you mentioned that you’re not a behavioral psychologist. But you brought up some very important issues, which you clearly understand. That if you’re, if all you’re doing is taking, taking, taking, it feels like deprivation.

But if you can substitute, if you can take away the pleasure from the donut and substitute it with something else, whatever that something else may be, then you’re on the road to accomplishing a longer term success with that. And the hope is for people with cognitive impairment or with mental illness, that improved brain function, improved psychiatric and mental health is one of those carrots.

That you feel better and then you can exercise more and then you can engage in more creative activities, or that those are the carrots. I use carrot, but those are the benefits to the low carb carrots. Those are the benefits to replace, which are quote unquote, taking away.

So, you clearly understand the concept, and and that has to be part of it. 

Stephen: 
You mentioned talking to Matthew Phillips, and I know of Matthew. I’ve corresponded with him, but I haven’t actually spoken to him. But he’s worked with both Parkinson’s patients on a ketogenic diet and Alzheimer’s patients.

And I’d be very interested to know whether you had the same experience as us, which is that the Parkinson patients are easier to recruit and easier to maintain. The retention on the study is easier than it is with the Alzheimer patients. They’re basically the same age. So, it’s not age alone, but I think the difference is that the Parkinson patients, if they’re improving, can actually see that the tremor is going down or that they’re actually able to write something or hold their spoon for their soup or whatever it is.

I’m not sure, and I’m sure that’s a motivating factor because the quality of life, they can feel the difference, whereas with Alzheimer’s disease, the improvement that may be occurring may be perceptible to the patient themselves. Probably more likely to their loved one or their caregiver who can see improvements that the patient themself doesn’t even notice.

So, how do you motivate the person who doesn’t actually perceive the benefit yet? 

Bret: 
Yeah, great question. Great question. Yeah, really interesting. That’s where having a care team and having loved ones and a family and a support system can be so important. So, it’s not just change what you eat. It’s change what you eat, have behavioral modifications in place, have a support system.

It’s all part of it, which is a lot harder than just popping a pill, right? It’s more involved than just taking a drug. So, we can see why there’s a higher, a steeper on-ramp maybe to adopt it. But in the long run, probably so much more important than just taking medication. So, I think this has been a wonderful journey to hear about you and your beginnings and how you progressed through this field and how the field has progressed.

And we heard about your project that you’re working on in the residents. So, what else are you working on? What can we expect from you in the near future as you move on with your research? 

Stephen: 
Two things really. one is that we learned, again by accident, that exercise helps get ketones into the brain in Alzheimer’s patients.

I presume that’s also true in healthy individuals, but we don’t know that for sure. So ,we were struck immediately by the opportunity to combine the supplement, or the ketogenic diet, plus exercise. Again, this is not a single silo approach to the disease that ketones can be generated by one technique, but their uptake can be improved by another technique, which should be the exercise.

So, combining the two. So, we’re doing a, pilot study in Parkinson’s patients with a ketogenic supplement plus exercise. And the same thing in Alzheimer’s patients. We’re going to be analyzing the preliminary data later this summer, and hopefully, we’ll have something to say about that this fall.

So again, to multimodal, I guess is the term we would use, and these things are. Ketones can’t do it all. And they shouldn’t be seen as something that is sufficient by itself. It should be combined with other approaches to your health. Because even if there was no problem getting ketones or energy into the brain, exercise, of course, is beneficial for health.

So, it’s not just one or the other two together. The other thing we were impressed to learn, again a little bit by accident, is that when you have a tracer for ketones, you can look at it, where it’s used in the body. We had been focused on the brain, pretty much above the neck, as we say.

We decided to look below the neck one day and found that the heart is extremely actively, metabolizing ketones as is the kidney. And so, we’re ruminating about what kind of projects we can do to study heart failure. And there’s already publications out there suggesting that ketones could be beneficial in diabetic heart cardiac failure.

And so, is this a question of fuel utilization and fuel strategies, fuel-based strategies, metabolic strategies? As for the brain, is it actually a similar situation to that in the brain? The difference being, of course, that the heart prefers to use fatty acids as fuel and the brain does not.

The brain essentially cannot use fatty acids. For all intents and purposes, doesn’t use fatty acids. Specifically, we’re looking below the neck, and there may be some interesting things that we can learn. It’s still a bit, physiological, a bit exploratory, but, there could be some opportunities there as well.

Bret: 
Wow, very interesting. I love to hear all that. So hopefully, we can have you back when some of this research starts to play out and you get some results. We’ll have you back on at Metabolic Mind here to discuss the results and see. 

Stephen: 
Be a pleasure, Bret. Absolutely. 

Bret: 
Oh, great. Thank you for taking the time. Really appreciate you sharing your journey with us. 

Stephen: 
You’re welcome. Thanks. 

Bret: 
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