Dr. Patrick: What do you think about a ketogenic diet for the treatment of neurodegenerative disorders like Parkinson's and Alzheimer's disease?

Dr. D'Agostino: I think there are different subtypes of Alzheimer's disease. Again, I think the etiology of Alzheimer's is complex, and there is probably a metabolic phenotype that Dr. Bredesen talks about like in his book. And I think that phenotype would be very responsive to the ketogenic diet where, I don't know, you would potentially screen for these patients by doing an FTG-PET scan. And if you see, you know, there's like brain atrophy, but if you see a dim PET scan, then a metabolic intervention may be a good, you know, approach for that.

But I can tell you just by communicating with hundreds of patients over the years, the ketogenic diet works remarkably well for some patients and has no effect on others. I don't think it's ever hurt or decreased anyone's cognitive, you know, capacity or anything that I'm aware of. I get biased feedback and people are telling me that it's working, but, you know, I've seen it not work too. Dr. Mary Newport was one of the people that really inspired me in the beginning. I actually brought her to University of South Florida, and she actually gave a lecture. She used to lecture for some of my classes. And at the time...the early times she would bring her husband, Steve. So I don't know if you know that there was a case report written on the use of beta-hydroxybutyrate ester as a therapy. And this case report was her husband.

And I witnessed that her husband...she had many more years, well, you know, years maybe like five or six years just from an outsider looking in. It seemed like she had that amount of time extra with her husband to spend because of the ketogenic intervention. The early part, it was just coconut oil, and then she realized that coconut oil had medium-chain triglycerides and then found the patent by Accera, AC-1202. And the active ingredient was caprylic triglycerides. So she went out and bought MCTs and then had an effect, but then learned about the ketone ester and the ketogenic diet and was administering that, and that was helping him.

When 2009 she was a guest speaker in my class and then we went out to eat, and her husband was shaking with Parkinson's disease-like symptoms, he had Alzheimer's disease. And then he had a vial of MCT and coconut oil. And when he consumed that, within about 15 to 20 minutes the tremor stopped and he became animated and was commenting on our conversation. So when I saw this in 2009, I realized that he was not really...it wasn't the food he was eating. He consumed that supplement, it elevated MCTs in his blood, which can also cross the blood-brain barrier but produce a state of hyperketonemia, and that acutely stopped the tremors he was having and he became more animated. And that was...

Being in contact with her and seeing this and witnessing it and also seeing his clock test and Mini-Mental Status Exam or State Exam convinced me to go in that direction for my research. So there's no doubt he was a metabolic phenotype, but he was also APOE4 positive, so which is very interesting, right, because we talked about, you know, different dietary interventions. So there was no doubt.

In the study of Accera in AC-1202, the APOE4 phenotypes were the ones that were not responsive to hyperketonemia, but he's APOE4...and he was responsive, and I saw it with my own eyes, and then that motivated me. Actually, the first study that we did was an Alzheimer's mouse study at the Alzheimer's Center. And then I developed the ketone ester because the funding agency did not want to look at the diet per se. So we focus on the ester later in the seizure studies.

Dr. Patrick: It seems like, you know, in particular with some of these neurodegenerative disorders like Parkinson's disease, I mean, you mentioned the tremor that, you know, the standard care of treatment, you know, like carbidopa-levodopa [SP], there's a lot of terrible side effects with time. And if there was another possible either adjunct treatment or alternative in some way or something, that it should really be explored more. For example, if you could. I mean, ketogenic diets are so widely accepted now for epilepsy. Like what about some of these other brain disorders? Is there any movement in research to kind of push to our understanding of whether or not ketosis is going to be beneficial for other types of brain disorders?.

Dr. D'Agostino: Yeah. It's so much easier to do a ketone supplement as opposed to a ketogenic diet for a...randomized controlled clinical trial is very hard with a ketogenic diet, right? But with a supplement, you can have a control, you can do things. So, I think those studies are happening, and we know that, you know, just by virtue of the ketogenic diet altering brain metabolism, brain pharmacology, we know...I mean, I observe early on that this is going to be important for many different neurological disorders and cancer too.

So, that's why we got steered towards, you know... So I didn't want to initially, you know, study cancer, but the data was so compelling that we should at least test this. And it became a whole another track in my research, you know, that we're doing in the lab. I think we are, but it's slower to go in that direction. And we really do need clinical trials before we can start prescribing these things to people, the ketogenic diets or the supplements. I mean, that's happening now.

But there's groups of people getting together...you know, there's a group that I'm involved in that's associated with metabolic psychiatry, and they are looking at dietary interventions for a broad range of psychiatric disorders. And that could be depression, that could be bipolar. Even eating disorders like anorexia is under the umbrella of a psychiatric disorder. So there's a lot of potential interventions there. And there's clinical trials, but the data is not there yet to, you know, be able to prescribe this to that.

Dr. Patrick: I mean, people are out there experimenting with ketogenic diets. There's ketone supplements that you can buy on Amazon. There's a certain element of, you know, there are families out there that are wanting to try different lifestyle, dietary changes. Talking to their physician about them is, you know, obviously recommended, but I mean, they're doing it, they're trying them. And I can tell you like so my mother has...she has the different types of tremors, essential tremor, she's got orthostatic tremor, she also gets migraines. And she did do the ketogenic diet with me. Somewhat she like cheated a lot more than I did. But I also have given her ketone supplements, and it's noticeable. And it's the reason why she even tried to...was wanting to try the ketogenic diet because she's very much addicted to refined carbohydrates. But it, I mean, noticeably stops her essential tremor and somewhat her orthostatic, which is her legs when she stands still, but noticeably the essential tremor and the migraines.

And this is totally anecdotal. So I'd love to hear your thoughts on it. She will take a ketone supplement. Ester has worked for her and ketone salts. So she's done the Ketostart, and it totally takes away her migraine, which is phenomenal because I'm not a big fan of the migraine medicine that she used to take. But she gets migraines that are debilitating. Like she can't...

Dr. D'Agostino: Oh, yeah, good rationale for migraines. Yeah. So, yeah, I get, I mean, a lot of emails about that. I try...because I'm a researcher, I go in the other direction and try not to oversell it as much as I can because...

Dr. Patrick: Totally.

Dr. D'Agostino: Yeah, I mean, that's just not very academic. So, I get so much feedback and I'm so excited. I want to cut and paste things and put it on social media about responses because people even send blood work or test results or their doctor. But I'm very cautious to do that because I know the power of placebo, I know the power but... I know what I saw years ago. The stopping of tremors and becoming animated was not placebo because the patient at the time didn't really know that he was...what he was taking, really. I mean, he was pretty far advanced.

But in regards to migraines, a Ph.D. student by the name of Dr. Elena Gross. So we wrote a review together, which kind of highlighted many of the benefits associated with migraines. So she was a person who had crushing migraines and discovered that the ketogenic diet and then later ketone supplements could recapitulate that and actually help to manage her chronic migraines that she had. And it was likely just like the ketogenic diet for epilepsy is working through multi-modal mechanisms, so by probably increased GABAergic tone, increase brain blood flow.

Some people get migraines because of like an increase in blood flow in some people because of vasoconstriction. And we know that the ketogenic diet and exogenous ketones increase adenosine. And from our metabolomic data, adenosine, I was not really interested in it at the time, was like many fold higher relative...it was a thing that was really hot on our metabolomics data. I was like, "Oh, this is very interesting." So, I recognize adenosine as a very powerful vasodilator for cardiovascular, you know, physiology.

So, when you fast or even when you go on a ketogenic diet, when you fast, blood flow to the brain can increase by 30%. So it's an acute. You can acutely elevate it and probably through this adenosinergic mechanism. So there's adenosine, there's probably dramatic effects on brain blood flow, on, you know, neurotransmitter systems, energy systems. And also neural inflammation can trigger a seizure.

I don't like to go to anecdotal evidence but I have...a lot of people will contact me that have like herpes simplex or shingles or different things where the virus like attacks their body, and the first sign that they get is like a crushing headache. And then they get like full-body inflammation, and then they get like sores if it's like shingles or something like that. And they'll start fasting or they'll acutely use ketone esters or ketone salts. Actually, they've been using...I've been recommending it and it's like, "Okay, please, give me...you know, give me feedback." And I've been giving them recommendations or not recommendations. I've been suggesting this as a potential way to mitigate the inflammatory cascade, and the feedback has been pretty remarkable that they can basically stop, you know, an episode from...you know, like shingles or herpes simplex.

And the same thing happens. They get crushing headaches, and then usually, that's a sign that the virus is starting to shed, and it produces, you know, changes in the brain. Systemic inflammation contributes to neuroinflammation, which contributes to the headache, and then usually you get the cascade kind of after that. So, it has worked through a variety of different people, and people get headaches for different reasons. So I think it's kind of like Alzheimer's where you're going to get...you know, a certain phenotype will be more responsive to...

And I probably should mention that there's products on Amazon that people are using, ketone salts, where they take it and it gives them a headache. I think I've taken some of these because, you know, I try to test as many things as possible, and there are supplements out there, quite popular ones, where I consume it, and then I just get like a headache...almost like a caffeine headache or something like that after that. That's a very reliable sign that there's something wrong with that supplement. So, if you're getting headaches from supplements, and I've gotten quite a few emails about this, so I know there's listeners out there listening to this, I would say change the ketone supplement that you're taking. And it could be the electrolytes, it could be contaminants, purity, potency, tolerability, gut issues. If it disrupts your gut, that could contribute to a headache. But I am firmly of the opinion that ketogenic diet and fasting. Fasting was also used for headaches. So ketogenic diets, fasting, and exogenous ketones can be used to manage migraines.