A 40% Energy Rescue for the Aging Brain in Clinical Trial | Dr Stephen Cunnane

[00:04] BENEFIC trial. So the So the theory is, right, that we and the root cause is that the glucose is not taking up, but we can kind of address it with uh ketones.

[00:18] So you ran a trial, the BENEFIC trial, where you were you were giving people uh exogenous ketones, well, MCT oil. So could you

[00:30] trial? You What was the design? How many people were there? And what was uh some of the key outcomes? So the BENEFIC trial was um I think it still is the the longest

[00:43] control trial of of medium-chain triglyceride in mild cognitive Um it was funded by the Alzheimer's Association of the USA. Um and we had a ceiling, we had a a budget that allowed us to study

[00:57] call completers, people who have completed the intervention, uh in both groups. So a placebo group and and an active group. And I think we had 19 in one and 20 in the other. Um and it was expensive because we were

[01:11] doing the brain PET imaging, the glucose and the ketone uptake at the start and at the end of the study because the purpose was a metabolic outcome. The purpose was to establish to what extent have we improved the

[01:25] metabolic status, to what extent have we reduced the brain energy gap in mild cognitive impairment. Cognitive outcomes were of interest and beginning and then 6 months later, but they were a secondary outcome because we

[01:39] knew the study wasn't powered to uh be sure about uh whether or not we were onset of Alzheimer's disease in these patients. So the metabolic outcomes showed that the ketones were getting into the brain.

[01:54] They showed that the uh that uptake of ketones was was variable. Some people had a big improvement. Some people had a smaller improvement. And the improvement on cognitive outcomes was positively related in terms of

[02:09] memory, in terms of executive function, and in terms of language to the extent to which we reduced the brain energy gap. That's what the first paper of of benefit paper published in 20 19

[02:23] Right. And these were people with MCI. It's kind of clinical Yeah, I didn't impairment, which means two criteria for that. Three criteria.

[02:36] They had to be over 55 years old. They had to have a subjective memory complaint, which means I'm worried about my memory, yes or no. If the answer is even if your spouse thinks that you definitely should be worried about your

[02:50] your memory, if you say it's no, then you're not eligible. And the third is that on of the five major domains of cognition for which we have the battery of tests that we do at the start, they have to be

[03:04] one standard deviation below the normal value on score for the score on at least one of those domains to be considered objectively memory impaired. So, a mild cognitive impairment, any one

[03:19] of those five domains. Okay. And what was the intervention that these people were given? They were given 30 g of medium-chain triglyceride per day.

[03:33] So, when we got funded by the Alzheimer's Association, we had proposed that we were going to make this emulsion of a medium-chain make this emulsion of a medium-chain triglyceride in in cow's milk in in in

[03:45] low-fat cow's milk. Um we had never done that before. And we weren't quite sure how to do it. We weren't sure how long it was going to last. We we got up to speed reasonably

[03:58] well, but we ended up with a sterilized product that people got an emulsion emulsification of 30 g of medium-chain triglyceride in 250 mils of milk in each A a cup. In American terms, a cup. A 250

[04:14] ml of of this drink, half at breakfast and of of this drink, half at breakfast and half at supper. reasons. Our preliminary studies suggested that most people weren't going

[04:28] to take more than that, weren't going to tolerate more than 30 g a day. that and let's hope let's cross our fingers that the you know, enough people are going to finish the study that we can actually interpret the results." We

[04:41] didn't know the extent to which 30 g of medium-chain triglyceride would help correct the brain energy gap cuz it had never been measured. been good to know before we'd started, but you know, sometimes

[04:55] uh you don't have all the pieces of the puzzle ready to to to to ask you know, to before starting a what was for us a major clinical study. It was a still a us. With the PET imaging and the supplement

[05:09] blood samples, um it was quite an involved uh study for us to do. Did you Did you look at how much Did you Did you look at how much the energy increased? The brain energy I

[05:24] did What was that? So, I I I'll give you the the the it has to be qualified by the what I'll say afterwards. So, the the gap was reduced by about 30 to 40%.

[05:39] So, the glucose should be going in it's down about 7 to 8% from where it should be in in a cognitively healthy older person. And we we improved that to down by down by about 4 to 5% instead of 7 to 8%

[05:56] roughly speaking. The but that's that's difficult to um to generalize and that's why I'm sort of hesitating because when you take a dose of these ketones of of the MCT, the ketones go up and but they'll be

[06:11] back down within 2 and 1/2 to 3 hours. So, the degree to which you correct the energy deficit depends on where you are on that curve and at the peak of the ketone levels in the blood, we're correcting about 40% of the energy gap.

[06:24] But for the rest of the time we're we're correcting less than that. supplement, you get a peak maximum of maybe for 15 40% of the energy gap, but otherwise you're contributing you're correcting

[06:39] you're contributing you're correcting zero zero to maybe 20%. So, over 24 if we improve the reduce the brain energy gap by more than 10% I'd be surprised. Right. So, I was going to ask why split

[06:53] Right. So, I was going to ask why split the MCT into two chunks? Was it A to give two peaks or was it to give two peaks or was it to reduce gastric possible gastric problems? Both. Both. Even if there were no

[07:06] gastric problems, we would have split it. We would have split it more than that, but we were strongly advised not to try to to uh re- require people to take it more than twice because it's just too much annoyance during the day

[07:20] and if you want to go out and play golf this afternoon, you've got to bring your know, you're going out on a picnic. All all the reasons all the good reasons people have for forgetting it or not not wanting to bother. So, two we figured

[07:33] was the most we could expect twice a day. Um and there were would have been side effects, so we you reduce the side effects, but that could all of them started out of a smaller than those than the 15 g at breakfast

[07:48] and 15 g at supper. They all started about five and within 10 days or so, they were they ramped up and and the intestine and the microbiome seems to adapt under those circumstances better than going in cold turkey.

[08:05] a C8 and C10. Yes. Yeah. Can you go into any more detail? We What were the percentages and how [clears throat] kind of sure are you that this is or how how strongly do you

[08:19] feel that this is perhaps the best mix to uh create ketones? Be- Because basically the MCT goes into the liver, right? And then you create ketones from it. Yeah. I So

[08:33] Well, it it it So, and back in 2015 when we started the study, when we got funded, uh there were no alternatives. There was nothing that was available to to replace them or if they were, they

[08:46] we weren't aware of it in in Canada at the time. And we have a regulatory Canada, which uh regulates the use of of of

[08:58] natural food products, they call them. So, a ketone ester or a ketone salt would have to receive Health Canada approval to be used in a clinical study. Whereas, MCT were already on the market in Canada. So, the those were the two

[09:12] logistical reasons why it it it was the it was the the product of choice. The mixture that we used, I didn't know at the time that C8 and C10 actually had a different ketogenic effect. So, C8 is moderately more ketogenic than C10.

[09:26] Uh but the two of them together were over 90% of the MCT. Uh 55% and and 35% I think were the ratios for or are percentages for C8 and C10.

[09:38] it's sort of thing you should we should have known beforehand, but we didn't than C10. Um and but I'm glad we ended up using Um and we were able to produce a placebo, which is is

[09:54] absolutely essential in this sort of study because so much of the evaluation is is not subjective, but it's it's open to influence. When when you're sitting across the desk from me doing your test uh your memory test, your trail making

[10:07] uh your memory test, your trail making test um for instance, um it's it's unconsciously, it's easy for you to look for help from me or for me to offer help for help from me or for me to offer help from you to you, whether it's time or uh

[10:20] something and it if and that's going to happen. you're on and I don't know and you don't know which product you're on, then it it it all comes out in the wash. Uh and and the the subjective effects of

[10:35] Uh and and the the subjective effects of having a person-to-person available for for uh more ketogenic uh um exogenous ketones that are available today. Um you you can make your own placebo for the ketone

[10:50] esters uh and for the for the salts um in-house as we did with the MCT, but um it wasn't available at the time anyway. So uh we were one of the first to do

[11:02] So uh we were one of the first to do this.