If Alzheimer's is Type 3 Diabetes, Is This Fuel The Fix? | Dr Stephen Cunnane

[00:05] >> [clears throat] >> I believe that you coined the term the brain energy gap. I mean, people were looking at ketones and and and how they affect brain energy before that, but kind of the brain energy gap

[00:18] as the potential cause for mild cognitive impairment and Alzheimer's was driven by yourself. So, could you explain what is the brain energy gap and and how does it kind of lead to MCI and and other

[00:33] lead to MCI and and other neurodegenerative issues? what we do, uh Richard, the brain energy gap. I I'm not sure if I coined it, but uh we realized that that's what we were dealing with and uh

[00:47] what I think is important to understand is that um there's a problem getting the main fuel into the brain as we get older for most people. Uh it's not universal, but it's it's quite widespread. And the main fuel

[01:01] is glucose. But, the brain is a hybrid car. So, it's running on two fuels that are complementary. The second fuel being ketones. Uh and

[01:16] the energy gap was just assumed to be a function of the brain cells that were supposedly dying as the the Alzheimer's disease uh evolved and progressed and advanced. Which is is is logical. A dead cell

[01:31] doesn't need any energy. So, um if the cells are dying, then you'd expect to cells are dying, then you'd expect to see less fuel uptake in general. But, it's in general. So, that should apply to ketones as well as to glucose.

[01:45] And we set out to establish whether that was the case. So, how do you do that? Do you use uh what's called PET imaging, positron emission tomography, which is familiar um

[01:58] to to people to physicians in who are studying cancer in particular cancers which are very metabolically and there's a form of tracer it's called a tracer

[02:11] a tracer for glucose which is taken up by tumors that's got a tumor in it and it's easy to see It's also been studied we studied the metabolism of energy metabolism in the

[02:25] heart and in the kidney and in in the brain and elsewhere so it it's not just for cancer studies. And what FDG it's called fluorodeoxyglucose is the tracer or FDG.

[02:39] And that tracer showed over 40 years ago at the dawn of PET imaging that there was a problem getting glucose into the parietal cortex just above the ears as parietal cortex just above the ears as Alzheimer's disease developed.

[02:55] then you assume well if that's the main fuel then then that's a a general global problem and we said well ketones can be are are generally a minor fuel but they can be the major fuel if you're fasting or if you've been starved for an

[03:08] extended period of time which has been done in metabolically in in in medically controlled studies for obesity for instance 40 40 day starvation has gone out of style these days but it was relatively common

[03:24] lose weight under medical supervision and under those circumstances it was of the brain. They replace that declining supply of and they are a a critical supplier so that's where the idea of the hybrid

[03:39] brain comes from the hybrid car. There are two fuels and the ketones are to to replace the glucose. So if there's a problem getting glucose into the parietal cortex and you have a method of measuring the uptake as well as the

[03:53] then you can compare that and you can establish be able to take up the ketones either. And what we showed with the PET imaging technique for ketones and for glucose,

[04:07] we repeated what had been shown umpteen dozen times with the glucose, the FDG tracer, but the ketone uptake was normal. And we were sort of impressed and intrigued, excited,

[04:21] but worried as well because it seemed a little implausible. And we repeated it. We also showed that if you gave a source of ketones with medium-chain triglyceride to an Alzheimer's patient, the uptake of

[04:35] brain. It's not just that the trickle of ketones was still present, but they those cells could actively metabolize more ketones when they were available. Well, then we started to get excited. And then we came across studies that had

[04:50] used different techniques which showed the same thing, that in fact, this is a robust observation that is not just an imaging-based method, but other types of So, I think that's

[05:03] that's what drives the concept of the brain energy gap. Yes, there's a problem getting glucose into the brain and it gets worse as Alzheimer's disease develops. So, the ability to take up that glucose and use it goes down. And

[05:16] that's what the gap is. And what we're trying to do is say, well, if ketones can be taken up normally by the brain in the same individuals in exactly the same how can we reduce that brain energy gap by providing a source of ketones to

[05:31] those individuals? >> Is there So, I believe that the brain >> Is there So, I believe that the brain uses less energy as we get older. difference between the way this happens in

[05:45] Alzheimer's and just normal aging, or is it just a kind of a scale and one side has even more like energy gap than normal aging? >> Well, it it's it's a yes, you're right. There is a trajectory downwards

[06:02] in the utilization of glucose and in some ways the older brain is more efficient for the same number of grams of glucose. You actually get more cognition out of it. Um That's what That's the positive spin on

[06:14] it. Um And that trajectory gets gets more acute in in mild cognitive impairment. In in healthy older people with mildly reduced glucose uptake, we're talking about a difference of 5 to 6% less than

[06:30] than than a younger adult. And again, it's I was a bit facetious, actually more efficient or it could be that it's it's actually got less reserve, less wiggle room to to to do what it should be doing.

[06:42] Um So, that's there's less redundancy. But in either case, that 5 or 6% is not in the parietal cortex. It's primarily in the frontal cortex. For better or for worse, it's not in the same areas in MCI. So, it's it's

[06:56] quantitatively more severe, more exaggerated as mild cognitive impairment develops and the regions of the brain that are affected are not the same. Eventually in Alzheimer's disease, it's it's a virtually universal problem

[07:10] except in the cerebellum probably and and in some deep subcortical nuclei, the deep nuclei in the brain are are less affected. there there's a nuance that we should put on it between healthy aging and and

[07:24] MCI. It's it's not the same change and and it's not diagnostic either, but it is it is different. uh Alzheimer's is sometimes called like uh

[07:40] type 3 diabetes because you you get glucose into the brain. Why is that specific to a region, the parietal region? So, I mean, I thought like diabetes, type two diabetes was

[07:53] kind of universal. Your body just didn't use glucose, not specific areas of it. it does the rest of the brain continue to take up sugar properly or not? >> Does the rest of the brain So, um first

[08:08] of all, um the glucose problem is not um it's not that the brain in Alzheimer's disease can't take up glucose. It's disease can't take up glucose. It's still taking about about 70 to 75% of

[08:20] the glucose it should be taking up. That's that's the good news. But, 70 to 75% of a you know, it's still 25% of what it should be, which is the bad news associated with the decline. But, it's not that the brain can't take up

[08:35] you wouldn't you wouldn't survive if that was the case. And so, why in the parietal cortex? That's it's a good question. I I don't think anyone knows. Um I mentioned the parietal cortex cuz it's easier to

[08:49] the middle of the brain between the two hemispheres, uh not far from the parietal cortex, it's called the precuneus. It's an area that is also affected. And so, there are some some deep brain areas that are are

[09:04] equally affected. But, the parietal, I guess is a bit more symbolic of of the disease, um rather than it being the exclusive region that's affected. exclusive region that's affected. >> So, how come ketones are still taken up?

[09:19] And so, yeah, how how do ketones work differently from glucose so that they can still be taken up by the brain and used as fuel? >> Well, they have a different transporter. It's a different type of molecule, and

[09:31] um is is not the same as as the one for Plus ketones, it's a relatively short metabolic path between the ketone body generation.

[09:46] about 10 steps. And each one of them will block if if steps would affect the glucose getting into the mitochondria. Um, so the bottom line is that the the transport of ketones seems to be normal.

[10:03] we we know, and that's not the PET assessed there are three enzymes involved in converting ketones to the carbon dioxide basically at the in into into the mitochondria, and those enzymes

[10:17] um from the studies that have been published are still normal. So, as the disease gets worse, I can imagine maybe affected uh eventually. And and some of those cells have died and some

[10:30] more will die, but there's enough of them that are alive to to do the brain's business, uh especially in the parietal cortex, which is affected, that you can slow that process down. Uh those cells are starving basically because they're

[10:43] not getting their main fuel. And I I and I think it's perhaps the time the moment to to bring up uh a critical point in this story, which is that utilization of glucose by the brain

[10:56] is dependent on the demand on the call for glucose from within the brain. in your blood that determines how much is going to be used by the brain. So, you can have a bowl of ice cream now and you know, eat 150 g of glucose, it's

[11:11] not going to change the availability of glucose in the brain by one molecule. Ketone uptake by the brain is driven by plasma levels of ketones.

[11:29] helpful uh if we're going to use uh ketone supplements to try to correct this brain energy gap because all it depends on is getting enough into the blood. And during our evolution, it makes sense

[11:44] system that the second fuel be able to react quickly to the absence of the primary fuel, or not the absence but a decline because you're trying to save that person from going unconscious, which is

[11:57] if there's not enough blood flow or enough oxygen. Um and and same is true for glucose. So, if the glucose starts to become limiting, the body's got to be reacting very quickly and the transport mechanism

[12:10] has to to kick in really quickly to switch over. It's not like a computer in your car that decides it can oscillate perhaps between the gas engine and the electric motors constantly uh according to some algorithm. Um in

[12:23] fact, the computer in your brain or in the body is insulin. Insulin is deciding whether your brain is going to use glucose or whether there's not enough glucose and therefore insulin goes down and that allows ketone

[12:36] production by from the adipose tissue fatty acid stores. The fatty acids are sent to the liver and they can be be converted to ketones when insulin is low. Uh you mentioned type 3 diabetes a

[12:49] moment ago. Um whether type 3 diabetes exists as a separate syndrome or or or not, the problem is still that there's insulin resistance in the brain and there's probably insulin resistance in the rest

[13:02] of the body as well. And that means that the body's not able to produce ketones because the insulin is blocking that. The insulin is telling the fatty acids, you stay in storage because we got

[13:14] enough glucose. The problem is the glucose isn't getting brain. So, the brain ends up in double jeopardy because the insulin resistance is blocking the uptake of glucose by by

[13:27] several organs muscle included but the brain to some extent as well but the insulin is also blocking the production and the liberation of the fatty acids that will become the replacement fuel as ketones for the brain.