Mitochondria's Role in Alzheimer's - with Dr. Matthew Phillips | The Empowering Neurologist EP. 79

Hello everyone, Dr. David Perlmutter here. Welcome again to The Empowering Neurologist. We've been talking a lot on the program about the benefits of being on a ketogenic diet. We are seeing the ketogenic diet being at least explored in the actual interventional treatment of many diseases, including neurological issues like Alzheimer's and, to a lesser extent, Parkinson's disease. There has been one study way back in 2005 involving only 5 patients with Parkinson's, but nonetheless, those being put on a ketogenic diet had a dramatic improvement in terms of functionality. Well, it looks like I've got some great news for you. A new study was just published, and it involved 38 individuals on a ketogenic diet with some very, very powerful results in terms of their functionality. So today we are going to talk to the author of that study. His name is Dr. Matthew Phillips. Dr. Phillips was raised in Canada. But now works full-time in Hamilton, New Zealand, where we will speak to him. He completed his general medicine and specialist— specialty training in neurology in Melbourne, Australia. His research is involved in exploring the feasibility as well as the effectiveness of various dietary interventions in creating changes in metabolism. And exploring whether or not these changes in metabolism will lead to improvements in terms of symptoms, function, and quality of life for people with various neurological degenerative conditions like Parkinson's and like Alzheimer's. So we're going to talk to him today about his new publication that just came out in the journal Movement Disorders. Here we go. Hello, Dr. Phillips.

Hi, David. How are you?

I'm just great. Thank you for joining us. Again, it's 8 AM where you are, right?

Yeah, it's 8:30, so close enough.

Good enough. All right. Well, I was very taken this summer, as you know. How the whole thing went down was really quite remarkable. I met your dad, and he told me what you were up to. I think he just sort of mentioned in passing that my son's involved in ketogenic diet and something called Parkinson's. And I don't know how these things end up happening, but, you know, because it's something that I've been really quite involved in over many years, and truthfully, we haven't really seen any good interventional trial except for the 2005 trial, which really was just a proof of concept of 5 individuals who did in fact have, as you know, a fairly significant improvement. And what we're talking about for our viewers, again, is the notion of your implementation of a ketogenic diet in a group of, I think it was 38 patients with Parkinson's disease. So what I'd like to do is first just maybe talk about what provoked you to look beyond medication and to look at something nutritional as it relates to this disease.

Okay, that's That's a bit of a long story, but basically I'm from Canada and I trained in Australia. And when I finished those many years of training, I was a bit— I just felt I hadn't found my way in terms of what specialty I wanted to do. As a neurologist, I could have specialized in stroke or epilepsy or Parkinson's itself or anything else, but really none of them seemed quite right. And to be honest, I wanted to specialize in a therapy rather than a disease. But I didn't know of any such therapy at the time. So I took a— I took 3 years off and I did, you know, a fair bit of work during that time and a lot of travel and a lot of thinking. And I came across, you know, other people doing different kinds of work. I came across some of your videos and, you know, the work of particularly Dominic D'Agostino and Jason Fung and And other like-minded people, Susan Messino, that it really intrigued me that maybe there was a therapy that could be used in multiple conditions. And the more I got into the whole approach of diet modification, not just to prevent but also to treat neurological disease, the more fascinated I became. And yeah, it just spiraled on from there. Resulted in a passion, I suppose, and here I am.

You embraced the— from likely a biochemical perspective, what a ketogenic diet can do, what ketones can do in the brain. This is not news. This dates back to the 1960s in terms of powering up mitochondria, etc. You then took it upon yourself to arrange an interventional trial of a group of patients with Parkinson's disease, and these individuals in your study were not on medication, as I recall, and you compared them to a low-fat diet. What— tell us more about the design of your study, and then we'll talk about your findings.

Sure. So I guess it stemmed from the 2005 study you mentioned by Theodore van Itallie, Who I believe is well into his 90s now. I was quite inspired by that study where they started with 7 patients, ended up with 5 patients finishing the 4 weeks of the ketogenic diet. And I think 2 improved by 20% in their motor scores, another 2 by about 45%, and one by like 80%. And it was on average sort of 40%, 45%. I thought that was— Just too significant to ignore. So for this trial, what I realized was lacking was a randomized controlled trial in this condition and actually pretty much any adult condition, even epilepsy. There's no good randomized controlled trial in adults with epilepsy. There's several in children. So what I wanted to do was create a ketogenic diet that I hoped people with Parkinson's could adhere to and hopefully even enjoy, and a low-fat control diet because that's the one that still has the most momentum in the mainstream medical establishment. And so unfortunately, it was quite difficult to do a control diet as a diet as usual. And actually, this is where a lot of people who do medication-based trials have difficulty because The standard for a medication-based randomized trial is a double-blinded placebo trial where you have 2 groups, one getting a medication and one getting a placebo, a fake tablet in essence, and that nobody knows, the patients don't know what they're getting and nor do the people assessing them know what they're on. And that's good for medications, but in diet you can't do that because you can't blind a person to their diet. People will know if they're taking in lots of fat or lots of carbohydrate in general. So the way you have to run a diet trial, if you do it like a medication trial and you do a control diet as usual, then there'll be no expectation of benefit because why on earth would you get better when you just keep eating what you've always eaten? Whereas the intervention group on the ketogenic diet or whatever diet you're testing— would of course have an expectation of benefit just because it's different. So you have to modify the control diet a bit in a diet trial to create an expectation of benefit and try to make that expectation equal across both groups. That's so that you get, you know, if you get a placebo effect, it affects both groups and thus any differences between the 2 groups can't be due to placebo effect because you've applied some expectation of benefit to both groups. So that was what we tried to do with our low-fat control diet. On top of that, protein really affects Parkinson's, specifically levodopa, the medication, the main one. And we had 47 patients commence the trial, and most of them were actually on medication. Only a few were not. And so in order to make sure that we didn't have— if you have a lot of protein, it will interfere with levodopa absorption. And so if, say, the low-fat diet had had A higher protein content than the ketogenic arm, then a valid criticism would have been, well, the ketogenic arm improved because they had lower protein and their levodopa was more effective. Valid criticism. So we had to control for that by making protein absolutely equal between groups. It was not easy and necessitated that we create a low-fat control group strictly controlled for protein. And so a bit more modified than their normal control. Yeah, so that— those are, you know, sort of 2 of the challenging aspects of it, I suppose.

Well, in looking at your results, it does look as if the ketogenic group clearly developed ketosis. I mean, you know, you were very able to demonstrate that. But more importantly, at least in terms of looking at the Unified Parkinson's Disease Rating Scale, You had some very intriguing findings. Can you walk us through those?

Sure. So I wanted— we wanted— the Van Itallie study looked at motor scores, and that was awesome. Parkinson's, it is a complicated condition, as you know, David. It has motor symptoms, which we all learn about in medical school: tremor, slowness of movement, bradykinesia, which is a typical kind of slowness. It's a reduction in amplitude of movement. As well as slowness. And rigidity and gait instability. However, and that's what sort of Van Itallie looked at, the motor symptoms, but there's a whole bunch more to Parkinson's. And the reason is that Parkinson's doesn't just affect the part of the brain responsible for motor movements. There's a small part in the brainstem called the substantia nigra that People focus on as the problem in Parkinson's, and that's true. The neurons in that region, they tend to die off. However, it's a disease of neurons everywhere in the body, and in fact, there's decent evidence showing it may commence in the neurons in the gut, the enteric nervous system, and possibly the olfactory neurons responsible for smell. And in addition to that, it will affect— it affects neurons that innervate the heart, the bladder, and throughout the brain. So Parkinson's is a disease of neurons everywhere, and that's why you get these motor symptoms, but you also get this huge array of non-motor symptoms. And non-motor symptoms are things like Pain syndromes, cognition problems, especially later on, bladder dysfunction, which is a real problem for some people, fatigue, depression is about 50% prevalent in Parkinson's, anxiety syndromes, and the list goes on. And it's these non-motor symptoms that dominate the quality of life in people with Parkinson's. Most people They present with a small tremor or something along the lines of the motor symptoms, but as the condition progresses, the non-motor symptoms become more and more prevalent, more dominant. And certainly what people really struggle with later on are those non-motor symptoms. And in addition to that, levodopa, which is our gold standard medication for Parkinson's for, you know, Half a century. While it generally treats the motor symptoms well, it doesn't have— it has far less success with particular non-motor symptoms, in particular things like fatigue and sleep, sort of daytime sleepiness, some of the pain syndromes. It's not good at bladder dysfunction. It's not very good, and it doesn't help apathy and cognitive dysfunction much either. So, I feel like I'm rambling on a bit here.

No, but I mean, I think the picture you paint is actually very intriguing, and that is, you know, the model has focused, as you rightly stated, on this unique pars compacta substantia nigra defect of dopaminergic transmission, and we'll put the dopamine back and everything will be fine, next patient. I mean, it's quite similar to the cholinergic hypothesis of Alzheimer's. Where it was noted there was decreased acetylcholine, and we'll give some cholinesterase inhibitor, and next thing you know, we've treated Alzheimer's. And neither really is treating the disease process. What you're describing is classic straightforward symptom management based on— That's right. Really focused, dare I say myopic, understanding of this disease. And, you know, even years ago, we noted that There was a mitochondropathy noted, or mitochondrial dysfunction, even in platelets that could be seen in patients with Parkinson's. And you're again correct in, you know, describing that this is far more than a motor issue, that there are bladder issues. Constipation might be the first symptom that people complain of. But, you know, cognitive issues, skin issues are very common. People don't talk about it, but I think it's taking us to a place of embracing the fact this is a big overriding problem in the body and let's address it like that, which is what a dietary intervention seems to do.

Absolutely. And so, yeah, that's why we wanted to check— we looked at motor symptoms and scores like Van Itallie, but we also looked at the non-motor symptoms. And the scale we used was this modified sort of disease, Parkinson's disease rating scale. It's sort of the, you know, touted as one of the best, if not the best, for rating the severity of the condition in its entirety. And yeah, so that's what we focused on there. And what we found was— Was quite interesting, I think. As you rightly say, the non-motor symptoms in the ketogenic group really improved quite a bit more than the low-fat group. And I must say, we treated both groups exactly the same as much as we could except for the fat-to-carbohydrate ratio. I mean, yes, we kept protein constant, But we also had ways to help people with the diet. We had weekly videos that we put online. We had emails twice a day. We played both diets up as potentially beneficial to equal degrees. And our assessors were SCALE-certified neurologists who had no idea which diet the people were on. And yeah, and we even assessed them. As you know, Parkinson's, the motor symptoms, the mood, and the effects of the levodopa can vary even from hour to hour. And so we had to assess these patients over the 8-week period of the trial on the same day of the week and at the exact same time, and I mean within 10 minutes. And we made sure that they took their levodopa and all their other medications at the exact same time before each assessment. We verified that. The patients were amazing in this trial.

Well, your results were really outstanding. And, you know, it's— you found improvement across so many domains, and it takes your breath away a bit when you talk about the success of this salubrious dietary intervention anyway, good for them anyway. I mean, when you watch their A1Cs come down, etc. But that said, why do you— or are you noticing that, A, there might be pushback, or B, people just in the field don't seem to want to embrace what you've discovered?

That's a really good question, and it's something— I anticipated and in some ways has come to fruition. I guess I just want to take a step back. I think in order to do trials like this, and I certainly don't, you know, want to bring any light on myself here, I think you have to be— to step out of the framework that we're taught, you have to be Perhaps a little bit brave, and I think definitely a little bit mad. And when you do that, when you take your ship a little bit away from harbor, out into the sea a bit of exploration in terms of a different concept, which is what ships are built for anyways, then you're going to get pushback. And I think that over the 2 and a half years of the, you know, the conception and execution and writing up and publication of this trial, I think initially, yes, I mean, there was of course blowback from some colleagues. Some were very supportive. Some colleagues and other people in the medical field. And initially, it was difficult for me to adjust to that. But I think Over the 2 and a half years, I've actually learned to become more tolerant. And often, someone with a contradictory point of view has a valid point of view, and you have to consider it and actually use it to make your own. I've used some of those views to actually, I hope, made the trial design better. And, you know, a lot of valid criticism. But in terms of the— Yeah, go ahead.

I can tell you, I know what it's like being the odd man out, but moving forward nonetheless. Let's go to a place for a moment of the biochemistry mechanistically. Why do you suppose you had the results that you had, which were really quite outstanding?

Thank you, Dave. I think there are 2 approaches. One approach is to try and get your theory tight and then apply it to reality. Where I rely a lot on the groundwork of people like Dominic D'Agostino and other like-minded people who do all this basic research in animal models that allows us to take it forward. But my approach here was, I'm not sure what the diet will do for Parkinson's in people, if anything. And so I'm just going to try and apply it as best as I can to to the people, help them through it, help make it as tolerable and affordable and simple. Remember, you're talking about people with a neurodegenerative condition. Simple as possible. And let's see what happens. And let's be unbiased. And let's just measure everything. That's why I had 4 primary outcomes. Let's just measure motor, non-motor symptoms, medication complications, everything, and see what happens. Now, so my answer to your question is I don't know. However, There are good reasons to think that a ketogenic diet, of course, could help Parkinson's. One of the big ones, as we know, it increases intracellular ATP availability for cells in general, and that's one of the motivations or thoughts behind its use for epilepsy. It also may stimulate mitochondrial biogenesis, so it generally increases energy availability, and if energy— problems are a part or a big part of Parkinson's, Alzheimer's, other similar conditions, that's a good thing. In Parkinson's in particular, if you look at human autopsy studies, there's a complex of proteins in all mitochondria. And the mitochondria, as I'm sure your viewers all know, are like the batteries of the cells and they make the energy that keep everything going. Within those, there's a complex of proteins called the electron transport chain. It consists of 4 or 5 complexes, depending on how you want to define it, and electrons flow down that chain and produce the ATP energy for all cells. In Parkinson's, on autopsy studies, complex 1 is damaged or inhibited or reduced by about 30%. And that is actually for a neuron, which has a cell— is a cell type that has among the highest energy demands in the entire body, if not the highest. Then that's significant. A 30% reduction will really cause a problem in ATP production. The ketogenic diet's power, the ketones produced by it, can actually bypass complex 1 completely and go straight to complex 2, as has been shown in previous work. And so the theory there was maybe if we create enough of these ketones that they can go straight to complex 2,

Well, you know, the mitochondrial defect has been talked about for a long time. The complex I issue was, of course, the underlying reason for the coenzyme Q10 studies. So one would wonder, moving forward, what might the contribution be to higher levels of coenzyme Q10? Well, I think that's a very good question. along with the ketogenic diet so that you can, to some degree, ameliorate the complex I dysfunction and then amplify ATP production with the boost from the ketones. Now that you've had these very positive results, what's next? Is there a larger study, or what do you plan to do?

I thought about this hard the last little while. I did have several People with different conditions on a ketogenic diet, case reports and things that I plan to write up soon. But what we're planning now is a larger study, but it's going to be in Alzheimer's disease. And I don't want to get too excited because these studies are extremely difficult. I mean, for me anyway, it's extremely difficult to implement. There's getting the ethics, there's getting the funding, there's getting a team, a good team together. I got lucky with this Parkinson's study. I got a great nutritionist, wonderful colleagues supporting me as my co-investigators, that is. And so you have to get enough patients together who are interested in this. Fortunately, that doesn't seem to be too hard. People are interested. And then you have to run the trial properly and And there are many ways it could all go pear-shaped. So the next plan is anyways to try in 2019 to run a bigger study, a longer study in Alzheimer's disease. We're creating a diet that doesn't have to be so restrictive because we don't have to absolutely match the protein between the 2 groups. And I'm really— people with these conditions, Alzheimer's, Parkinson's, as part of the process perhaps have a— A real sweet tooth and a need for some sweet kinds of foods. And so we're right now working very hard to create, in addition to healthy vegetable-based foods and whatnot, to create healthy sweet keto desserts for these people. So it's all about trying to make people— there's no point having an intervention if people can't tolerate it. And that's been the Achilles heel of the ketogenic diet for 100 years. Since Wilder created it in the 1920s, it may work well for epilepsy, but a lot of people struggle because it's not only socially difficult, but it's difficult to enjoy. And I really believe it can be difficult— it can be easy to enjoy. It's a great way to live, and as you say, it helps your diabetes markers and it's great against obesity and other— You know,

treating Alzheimer's with a ketogenic diet, who knew? Yeah. I would say that, you know, some have argued that our Paleolithic ancestors prior to the advent of agriculture were pretty much in a low grade of ketosis all the time, so they were protected, that that was the diet that helped reduce inflammation, helped power their cognitive development and cognitive function moment to moment. So it may not be as novel as an idea as some people would like it to be. So congratulations on your work, and I think it was so incredibly serendipitous that we got connected this way. I mean, it, it's just amazing how that all ended up playing out. So thank you for your time today.

Thank you, David. It's been a pleasure.

Okay. Well, what a dedicated individual putting together these trials. Looking forward to a new trial, interventional trial, in actually treating Alzheimer's patients by putting them on a ketogenic diet, hoping to override this mitochondrial energy defect that seems to be so prevalent in that and other neurodegenerative conditions. So, kudos to, to Dr. Phillips for doing such great work. We really look forward to hearing more from him in the years to come. Thanks for joining me. If you want to get more information about ketogenic diet, obviously go to our website, drperlmutter.com. I would also indicate that we are sending out a free informational newsletter every week. If you go to drperlmutter.com, you can sign up for that as well. Until next time, bye for now. Bye for now.