The Peter Attia Drive - #38 - Francisco Gonzalez-Lima, Ph.D.： Advancing Alzheimer's disease treatment and prevention – is AD actually a vascular and metabolic disease？

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

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00:04:01.960 thank you for taking a moment to listen to this. If you learn from and find value in the content I

00:04:06.840 produce, please consider supporting us directly by signing up for a monthly subscription. My guest

00:04:12.500 this week is Francesco Gonzalez Lima, a professor of neuroscience and pharmacology and toxicology at

00:04:18.480 the University of Texas, Austin. In this episode, we talk about Alzheimer's disease. In particular,

00:04:23.720 Francesco explains the vascular hypothesis of Alzheimer's disease, a hypothesis that his colleague

00:04:28.540 and collaborator at UT Austin, Jack De La Torre, introduced to the field about 25 years ago.

00:04:34.000 He makes the case that the central problem in late onset Alzheimer's disease is a progressive

00:04:39.380 neuronal energy crisis, meaning impaired blood flow to the brain and impaired mitochondrial respiration.

00:04:46.920 If the problem is an energetic crisis, Francesco argues, then we can improve the supply of energy

00:04:52.200 and blood to the brain. We could probably make progress in the prevention of Alzheimer's disease.

00:04:56.820 We of course get into great detail at about all of this stuff. And to paraphrase my friend and my

00:05:02.260 colleague, Richard Isaacson, who I've already spoken with on the podcast a while back, as you may

00:05:06.600 remember, and who directs the Alzheimer's prevention clinic at Cornell, if you have a brain, you don't

00:05:11.500 want to miss this episode. So without further delay, here's my conversation with Francesco Gonzalez Lima.

00:05:20.480 Francesco, how are you?

00:05:22.060 Fine, thank you.

00:05:23.100 Thank you so much for making time to see me on a Friday afternoon.

00:05:27.500 My pleasure.

00:05:28.060 This is actually my first time to the university. I've been to Austin many times, but I never seem

00:05:34.740 to be north of downtown. So it was beautiful to drive by the medical center on the way here.

00:05:39.160 It's kind of amazing. I haven't even been to a football game, which I hope to one day do at some

00:05:43.320 point. So how long have you been in Austin?

00:05:46.460 I've been here as a tenure professor for 27 years.

00:05:51.260 Wow.

00:05:51.440 Yes. And during that time, I started out in pharmacology and toxicology and moved to psychology,

00:05:59.560 just added that. Then the recruiting institution was the Institute for Neuroscience.

00:06:07.720 And now I'm a faculty also at the Department of Psychiatry at the new medical school.

00:06:13.080 And we were talking a little bit earlier, you describe yourself as a behavioral neuroscientist.

00:06:18.020 Tell me a little bit about what that title means. Why behavioral?

00:06:22.420 My original training as a PhD was in anatomy and neurobiology. And then as a postdoctoral fellow,

00:06:30.860 I tried to understand how the brain related to behavior. And I did that work as a Humboldt fellow

00:06:38.700 in Germany. And that was my introduction to the study of functional brain mapping and how we could see

00:06:47.660 behavioral functions reflected in brain activity. This was the time where we developed the

00:06:55.080 fluorodeoxyglucose autoradiographic method in that German group in Darshten that later became the key

00:07:04.220 to develop FTG PET, the first functional imaging technique in humans.

00:07:10.320 Yeah. It's interesting you say that because I noticed that a number of patients when I talk to them

00:07:15.140 don't understand sometimes the difference because I don't think physicians explain the difference

00:07:19.320 between functional studies and imaging studies. And I remember feeling very fortunate in medical

00:07:24.300 school during a radiology rotation where one of the residents sat me down and explained the

00:07:30.120 difference. And the PET, of course, the FGD positron emission tomography being a great example of a

00:07:36.140 functional study. It's not giving you anatomic resolution. It's giving you functional resolution

00:07:40.860 with respect to glucose uptake. And similarly, you would now have functional MRI, which is doing

00:07:46.500 the same sort of thing. And so, yeah, that's a very important distinction.

00:07:50.560 Especially important if you want to be able to determine a disease in a very early stage

00:07:59.600 in which there are no structural changes in the brain that can be seen at least at the microscopic level.

00:08:05.920 And having functional techniques, you're able to identify these functional changes even before

00:08:12.220 you have any other signs of the disease.

00:08:15.940 So, I know you're a gentleman who has spent time all over the place. You were born in Cuba. You left Cuba

00:08:22.460 when you were quite young. You spent time in Costa Rica, Venezuela. I mean, where did you-

00:08:27.720 Puerto Rico.

00:08:28.240 And Puerto Rico, of course. All of those things, at what point did it become clear to you that you

00:08:33.460 were interested in the brain? I think my father was a veterinary doctor. And originally, my interests

00:08:41.780 have to do with working with animals. But soon, I realized the nervous system was so important for

00:08:48.140 the entire health of the animal and the behavior of the animal. So, I started to move away from just

00:08:55.240 a more general interest to something that had to do more with the brain. But I would say my key

00:09:01.480 influence happened as an undergraduate at Tulane University in New Orleans, when one of my

00:09:09.600 professors, Dr. Joan King, dissected a brain in one of our classes. And this was an undergraduate

00:09:17.300 honors class. And it was fascinating to me. And I joined her lab to do an honors thesis, working on the

00:09:26.540 relationship between the brain, hormones, and behavior in animal models.

00:09:33.260 It's so interesting. I think back to my own time in medical school. There were clearly a subset of my

00:09:39.020 colleagues who were so captivated by the brain, which in gross anatomy really doesn't depict a

00:09:46.020 fraction of its brilliance, right? Unlike the heart, where certainly microscopically, there are things

00:09:51.540 about the heart that are relevant. You can't see the Purkinje fibers. You can't see the AV node or the SA node.

00:09:56.600 There's so much that is invisible to the naked eye. But for the most part, you can appreciate the

00:10:01.080 brilliance of the heart at the macroscopic level. But then there are other organs that, you know, on the

00:10:06.960 other end of the spectrum, get no attention, like the liver. I mean, macroscopically, it's just a lump of

00:10:11.860 whatever. But of course, what's happening inside the liver, to me, makes it one of the most

00:10:16.020 remarkable organs. But the brain is an organ that has such a unique look, right? Grossly, it looks so

00:10:21.580 distinct. The tissue looks so distinct from all of the other tissue outside of the central nervous

00:10:27.080 system. And also, to this day, I would say our knowledge of the brain must be far, far behind that

00:10:35.380 of any other organ at the sort of physiologic signaling level. I mean, is that a fair assumption?

00:10:40.840 Oh, yes. I agree completely. And I would say using the same analogies that you have, the heart,

00:10:47.620 you can think of it as a mechanical engineer, a pump, a hydraulic pump, whereas the brain is more

00:10:55.140 of an electrical engineer, where you have lots of circuits. And the liver, for that matter,

00:11:01.000 will be a chemical engineer, where we break down all of these substances that the body consumes.

00:11:07.300 I actually love that. I've never thought of what you just said. And that is a great way to explain

00:11:12.300 the different types of engineering. The kidney would be some sort of sanitation filtering engineer. I

00:11:17.220 mean, we could really, yeah, yeah. Environmental. Yeah. And so in many ways, the brain is probably not

00:11:23.080 only electrical engineering, but it's computer science engineering. There's so much going on there.

00:11:28.400 Right. You hit in a very important point. One cannot simply look at the brain the same way that you look

00:11:35.800 at other organs. Because of that circuit property, it allows the development of computational power.

00:11:44.540 So the brain uses the circuits, not just for communication, which is the most obvious function,

00:11:50.760 but to determine and compute outcomes that they are used to guide the other tissues in the body. For

00:12:01.240 example, the musculoskeletal system cannot do anything on its own without the commands that are the result

00:12:08.780 of computations from the nervous system. So all of our behavior results from how the nervous system

00:12:16.080 can process our experiences and our current situations. And it's become not in the same way

00:12:24.760 as a computer works that is a serial device. The brain is a very redundant parallel system where there

00:12:33.980 have to be a lot of convergence between different regions that are computing for that to be acknowledged

00:12:41.440 as the way to go in a behavioral point of view. So for a person listening to this who might not have

00:12:48.900 the luxury of knowing some of the nuances about the brain that you do, when you're talking to an

00:12:54.880 audience that is, presumably most people are interested in the brain because of brain pathology.

00:13:00.220 It's, you know, once a disease strikes the brain, everybody becomes well aware of how much it's doing

00:13:06.140 because the absence of that function leads to such an obvious downside. How do you describe for people

00:13:13.940 this notion of convergence and redundancy and overlap? I mean, obviously there's a very strong

00:13:19.540 evolutionary reason. What are some examples of those and how those things are, these processes are

00:13:25.560 preserved in terms of, because you use, I like the use of, I'm an engineer, so I do like the use of talking

00:13:30.280 about serial versus parallel processing. Maybe expand on that a little bit. In reality, all of the anatomy

00:13:36.640 is redundant and parallel. At least, for example, we have bilateral symmetry, you know. Everybody knows

00:13:43.940 we have two hands, two legs, two eyes. We probably could have done it with one eye, but the way the system

00:13:51.300 works is that it creates redundancy. And then, for example, the circulatory system is the same. You have

00:13:59.220 parallel blood vessels where you can get the blood from one point to another in more than one way.

00:14:06.320 And, of course, when you sit, when you put your elbow down, you can compress a blood vessel, but there's

00:14:12.500 still another route that can be used. It's like coming from the university to the downtown area. You have

00:14:21.120 many options to get from one point to the other. So, in the brain, this is maximized to its extreme. It's an

00:14:27.740 organism specialized for this large amount of communications. In other words, having so many

00:14:34.400 highways and avenues where information can go through. So, in that sense, differs from other

00:14:42.180 organs where you have a pattern that repeats itself, and the redundancy is only on that pattern. Here in

00:14:49.280 the brain, the redundancy is combined with the acquisition of new networks or circuit auctions

00:14:57.060 that are not possible if you only have one design. So, you have multiple designs. If you want an

00:15:04.480 analogy, for example, when NASA was sending the man to the moon, they have like a hundred computers doing

00:15:11.220 the same computation. And then they look at the output, and they see which is the output that is

00:15:17.660 repeated more often. And that's the one that those coordinates are the ones that they're going to pass

00:15:22.900 on. The brain uses that strategy, and that's what I mean by convergency. In other words, you have all

00:15:28.880 of these multiple parallel systems, and they are doing these computations, but only the ones that converge

00:15:34.960 on the same solutions are the ones that are acknowledged and move on for the next stage.

00:15:41.760 And when you look at other species beyond humans, how much of that redundancy do you see as you go

00:15:50.260 down the evolutionary chain or down the food chain, maybe is an easier way to think about it. I mean,

00:15:54.760 at what presumably, you know, chimps and cats and dogs are very similar, but is there a point at which

00:16:00.280 it very suddenly stops, or does it simply diminish to the point where, you know, when you're looking

00:16:05.480 at a simpler organism like a worm, for example, I don't even know what the nervous system of C.

00:16:10.520 elegans looks like. Well, definitely mammals and primates in particular, where basic plan is the same,

00:16:18.800 and most of the differences have to do with which of the networks are more developed than others.

00:16:26.160 So, in primates, we have the cerebral cortex becoming the dominant component in the brain.

00:16:33.260 This is, to a certain degree, the same thing in all the mammals, but then other regions of the brain

00:16:38.720 have more similar contribution. When you go down to, for example, erectiles or amphibians,

00:16:46.940 the midbrain, the mesencephalum, is the largest part of the brain, not the portion where we have the

00:16:53.860 cerebral cortex. And what that means, basically, is, in addition to this parallel processing that we

00:17:00.860 have, information goes through several hierarchical stages. And at every one of these stages,

00:17:10.160 similar processing is done, and you add an additional piece of information when you move it on.

00:17:16.780 For example, you can respond at the level of the spinal cord. That would be the lowest level of

00:17:23.480 response. That would be, for example, a reflex. Like, if you tap somebody's knee, you transiently

00:17:28.680 lengthen the patellar tendon, the knee kicks out to straighten it or reduce the length. And that

00:17:33.440 is happening outside of the brain. Yes. However, when you tap the knee, the information also goes

00:17:41.040 to all the levels of the nervous system. In that case, you saw the spinal reflex being manifested.

00:17:48.820 But the person still knows. Yes. They felt the sensation and they know what happened.

00:17:53.560 So the same was happening at different hierarchical level processing. So behaviorally speaking,

00:18:01.000 when we respond to a stimuli at very basic level, like what you indicated, like the spinal level,

00:18:07.780 we call it a reflex. So that would be the most basic behavioral response. But that means that you

00:18:15.180 are not seeing what is happening at the other levels. But for example, in a frog that is following

00:18:21.860 an insect, a worm as it's moving, the frog would orient to the movement. As long as the worm is moving

00:18:30.580 in the same direction as the long axis of the body, you have the same worm that is a fake worm where

00:18:36.920 it's moving in a direction perpendicular to the long axis. It's long axis. Yeah.

00:18:42.580 The frog will not follow. So the pattern isn't recognized. So if a frog sees a worm moving in

00:18:48.680 the normal direction a worm moves, it knows that pattern. If it sees the exact same food source

00:18:54.140 standing up and walking on the side, it's not going to pursue it. It's not pursuing it.

00:18:59.260 But in order to do that new computation, then you needed the level of the midbrain. So the midbrain

00:19:06.760 becomes now the point at where the decision is made and whether to follow and then eventually snap

00:19:14.200 and capture the worm. So the submammalian species primarily operate at that level. And they have well

00:19:24.140 defined. Instead of being called a reflex, we would call this like release stimulus. Release stimulus

00:19:31.020 creates that generates a pattern. There is a pattern generator that recognizes it. But then in mammals,

00:19:37.980 we have to move information to the level of the thalamus that is in the middle of the brain, but

00:19:43.900 higher than the midbrain. And then from there, the majority of the mass of the brain is in primates and

00:19:53.960 humans in particular is in the cerebral cortex. So we have to pass that information to the cerebral

00:20:00.600 cortex and then feed that back down to the output systems. So it might be a way of oversimplifying,

00:20:07.640 but one could think of it as the brainstem and spinal cord are responsible for these reflexes. For

00:20:12.520 example, we breathe without thinking because our brainstem allows us to. We recoil from pain without

00:20:17.640 thought because of these things. The midbrain took it up a notch by basically allowing for that stimulus

00:20:23.480 response. But the thalamus then becomes the gateway to the cortex where we can do this higher processing.

00:20:29.000 That's probably an oversimplification. And the main contribution of this thalamocortical system

00:20:35.480 is to allow us to inhibit behavior. In other words, not to respond in a more immediate short-term

00:20:43.160 manner. So the ability to delay a response and to try to compute what are the consequences

00:20:50.840 if we were to make that response. This is what really is brought up by our more elaborate cerebral

00:20:57.640 cortex. So the majority of the influence of the cerebral cortex on subcortical levels.

00:21:04.200 It's inhibitory. It's not excitatory. No. And engineers actually don't understand this very well.

00:21:11.160 When they, for example, try to create a prosthetic device to have somebody send neural impulses to move a

00:21:18.600 leg that is paralyzed. They try to create this as an excitatory type of phenomenon.

00:21:25.320 But what the brain is doing is not like that. What the brain is doing is inhibiting all possible

00:21:33.080 vectors of movement in a space and then selectively releasing some of them by sending an inhibitory

00:21:40.920 signal to that. Yeah. It inhibits the inhibitory signal, thereby selectively, quote unquote,

00:21:46.680 releasing activation. Yes. And when you do that, you have more control because you are actually,

00:21:52.600 for every movement, you're not just working as a puppet where you're trying to only emulate those

00:21:59.400 vectors. You're controlling all of the other possibilities. So you sort of carve a tunnel in

00:22:06.520 space, which are the only vectors that are allowed to be manifested. So the engineering of the brain

00:22:15.160 in this sense requires this more effort in order to achieve something that could have been achieved

00:22:21.800 by a more simplified system because it wants that control.

00:22:27.160 So is it safe to say that more of the pathology that we see in the brain occurs in the cortex than

00:22:35.640 in the midbrain? For example, Parkinson's, I guess, would be partially midbrain, right?

00:22:40.520 Primarily midbrain.

00:22:41.720 Yeah. Are there great examples of common pathology in the brain stem?

00:22:45.400 Yes. But from the point of view of dementia and neurodegenerative disorders with the exception of

00:22:54.680 Parkinson's disease, these are primarily cerebral cortex. This is where you see especially the

00:23:01.880 initial functional deficits and later on the atrophy and loss of tissue. But most of the diseases of

00:23:11.400 all age that affect the brain primarily target these cortical regions.

00:23:16.920 And that's obviously the thing that I most wanted to chat with you about because you and your

00:23:21.800 colleagues, you have a different point of view on Alzheimer's disease. And in many ways, it's when you

00:23:29.000 read your work or hear you guys talk about it, it doesn't sound that hard to believe. It's actually

00:23:34.280 quite a reasonable hypothesis. Let's start with the conventional thinking on Alzheimer's disease,

00:23:39.480 which needs to be caveated with the fact that there is no disease for which we have had a greater

00:23:45.480 failure in our ability to treat it than this one. Even cancer, which one could argue we're not

00:23:51.560 exactly hitting it out of the park on, we at least have some success. We can point to very,

00:23:56.840 very specific successes, not only in terms of prevention, for example, simply the recognition

00:24:02.520 that something like smoking could cause cancer led to an enormous reduction and a continued enormous

00:24:07.800 reduction in the onset of that disease, but also very specific chemotherapeutic regimens for a subset

00:24:13.880 of cancers, particularly liquid cancers. And now more recently, we've seen some real breakthroughs

00:24:18.920 with things like checkpoint inhibitors, uneven solid organ tumors. So at least with cancer,

00:24:23.240 we have some sense of we're making progress. Certainly with heart disease, we've probably made the most

00:24:28.360 progress. And yet with this disease, it appears we have not made a shred of progress. What is the typical

00:24:37.480 explanation for what causes Alzheimer's disease and therefore, by extension, what the path should be

00:24:44.440 to prevent it or treat it? You're completely right. We have not made any significant progress in

00:24:52.760 Alzheimer's disease research. This is the largest failure of the biomedical research enterprise in the

00:25:00.840 world during my lifetime. And the main reason is we have remained faithful to an initial observation that

00:25:12.040 was done or published at least in 1907 by Lois Alzheimer's that indicated that he saw these abnormal

00:25:20.680 depositions in the brains of an individual after that individual died. This individual was 51 years old when he died.

00:25:31.240 But Alzheimer's was actually a psychiatrist, not a neuropathologist like it's pointed out in books.

00:25:38.760 He worked in a psychiatric hospital. It was part of the original group led by Kreppling in Munich.

00:25:45.800 And they were studying mental illness. And in those days, it was believed that what we call

00:25:52.040 nowadays dementia was a form of mental illness. And he was surprised by this young patient that was

00:25:59.240 showing these early signs of dementia, you know, in his 50s. And already by the time he died, that person

00:26:06.200 had been suffering for many years. So what Alzheimer's described as in the brain of that individual has

00:26:13.480 Alzheimer's disease is not the same disease that is happening in older people. It's not the same 0.98

00:26:21.960 disease that is the most common type of dementia. And this is being the most basic misunderstanding

00:26:28.920 from the beginning. Historically, there was a competition between two groups, one in Prague,

00:26:35.560 in Czech Republic, at that time was under German rule. And Oscar Fischer published studies,

00:26:43.400 where, for example, he looked at 16 brains from patients that had what was called senile dementia.

00:26:51.560 That is the type of dementia that was showing up in people after they were 60, 70, 80 years of age,

00:26:59.480 not these younger individuals. And he described some of these same abnormalities that later

00:27:06.600 that Alzheimer's published, but for that single case. However, Krepling was a rival of that group,

00:27:14.680 especially about Fischer who was Jewish. And so he published in the first book that talked about

00:27:21.720 Alzheimer's, the first textbook of psychiatry that was published by Krepling. And then he say,

00:27:27.640 oh, what we're seeing in these old people, this type of dementia is what Alzheimer's described in that

00:27:34.680 younger individual. And from there on, there was a movement away from factors that were related to

00:27:41.800 aging and to say, this is a disease that is invading somehow. And it's not something that is building up

00:27:50.600 over the years. Of course, this is actually not the case. So nowadays they try to have a compromise and

00:27:58.040 say Alzheimer's disease, there is early onset or familial, which is primarily familial. There's some

00:28:05.640 evidence for inheritance. But nine out of 10 cases of what is referred to as Alzheimer's disease,

00:28:13.640 there is absolutely no inheritance or familial component, which is one of the greatest fears of

00:28:22.760 people when they have patients with dementia in their family. And not only that, it's aging related.

00:28:30.680 And because it develops very slowly over the decades, it provides an opportunity to intervene,

00:28:39.240 to determine what are the risk factors that are behind, and to do an intervention. If you take the

00:28:46.040 other approach, that this is a disease of these abnormal proteins, and it can happen early on,

00:28:51.960 then you have a very different strategy. So the whole field has been dominated primarily by what is called

00:28:59.720 the amyloid beta hypothesis. This hypothesis is completely, absolutely false. It has no

00:29:08.840 relationship whatsoever with what we see in the older people that develop dementia. It has a relationship

00:29:19.560 with some of these early cases that, like the one that Alzheimer's described, and they have a familial

00:29:26.200 component, and that there is a somatic genetic component. Let me just interrupt for a second to make sure

00:29:32.120 I'm understanding. This is obviously such an important point that I want to make sure I'm clear and that

00:29:37.960 the listener is clear. Now, the case that Alzheimer's found in 1907, I have to assume that was a PSEN 0.98

00:29:44.120 one or two mutation. That was what we now see accounting for less than one percent of Alzheimer's disease,

00:29:49.560 but it is probably the closest to a fully penetrant gene that results in Alzheimer's disease. Has that ever been

00:29:56.200 confirmed? Are there any biologic specimens remaining from that particular individual who was so young?

00:30:01.560 There are slides available, but it has never been confirmed. And the patient died in 1906 after many

00:30:09.320 years with this chronic dementia in that hospital in Munich. And he was deteriorated in every other

00:30:16.760 respect. By that time, he was unable to move and carry on on activities of daily living. So he'd been

00:30:24.120 suffering from this for many years. Which is not unlike what we can see in the rare patients that do have the

00:30:30.520 PSEN one or two gene, which is, it can easily take hold in the forties. I unfortunately have a patient

00:30:36.760 whose mother is, you know, debilitated in her mid fifties. Now it turns out she doesn't have the gene,

00:30:41.480 which was a surprise to a lot of us. We assumed because it had taken hold so early, but the autopsy,

00:30:47.640 the pathology that they could see, which at the time was limited to very gross things relative to

00:30:52.440 today. Gross for the listener. I don't mean gross as in disgusting. I mean gross as in visible through

00:30:57.400 a microscope. Was this the first time that amyloid beta was observed? No. The first time

00:31:03.880 was done by Oscar Fisher in the senile dimension. So Alzheimer's was basically describing a phenotype,

00:31:12.040 but without a pathologic explanation or characteristic. Yes. But because it was happening so early,

00:31:18.280 then it moved the people away from the idea that this has something to do with senility,

00:31:24.360 with the older deterioration that happens as a function of aging. So they say, oh no,

00:31:30.840 this can happen early on. So aging cannot be a primary contributor. So even though a very small

00:31:41.080 percentage of people that are described as having Alzheimer's belongs to this early onset, over 90%

00:31:49.880 of the research is focused on that group. And the reasoning is because it's the same disease,

00:31:58.520 which is a false premise. If we find out what's happening in the early onset, and we model that

00:32:05.320 in animals by doing this genetic manipulation, then we can fix the more common senile, older age,

00:32:13.800 late onset dementia. And that false premise is what has been driving all of these failures.

00:32:20.920 Because yes, they have been able to detect genetic changes. They can manipulate this.

00:32:26.360 I was able to work, examine the brain of the first amyloid precursor mouse model that was developed.

00:32:33.160 And one of the first things that I noticed in the brains, even before there was any amyloid deposition

00:32:39.240 in that model that they had inserted, it was a transgenic mouse model. They had taken away the

00:32:46.120 native gene from the mouse and replaced that gene with one that was abnormal for a patient with early

00:32:53.800 onset Alzheimer's. But even before that gene could start any observable deposition of amyloid,

00:33:01.800 these brains, by that very manipulation, were abnormal. They had severe atrophy in, for example,

00:33:10.520 the corpus callosum, the bundle that communicates the two hemispheres. And the region of the

00:33:16.280 hypocampal formation has lost one third of its volume. So the intervention itself may have altered

00:33:23.000 the resilience, if nothing else, of the brain. Yes. And of course, then these animals show all kinds

00:33:29.240 of behavioral abnormalities. But these things were happening even before there was any amyloid 0.95

00:33:35.400 deposition. So it was clear that having a gene with these abnormalities, even before you can see that

00:33:44.760 product building up is enough to distort how the brain develops. So this has been the main problem.

00:33:53.080 And because biology, just like when I started studying biology, my major was called cell and

00:33:59.160 molecular biology. And that became the dominant orientation in biology. So people who do this

00:34:08.040 research oftentimes don't have a very good understanding of the brain as a whole. And they

00:34:13.800 just focus at that molecular level. And in a way, they're trying to find the answer where the light is,

00:34:20.680 that is the light that they can use. And trying to ignore that this is really a disease of

00:34:26.760 all age that involves a long development. And that there is absolutely no correlation,

00:34:34.040 no relationship between the amount of, for example, amyloid beta deposition,

00:34:40.440 and the onset of memory deficits, cognitive impairment, or the progression of the disease.

00:34:47.480 There are brains of individuals that I have the fortune to examine here in Austin.

00:34:53.160 Hassan, primarily a neuroanatomist, a functional neuroanatomist. I collaborated with the neuropathologists

00:34:58.680 here. And the brains of these people who were cognitively normal after they died,

00:35:05.080 they couldn't differentiate them from the ones that were diagnosed with Alzheimer's based on

00:35:11.240 amyloid and neurofibrillary tangled depositions.

00:35:14.520 That's an enormous statement. It doesn't call into question the causality of amyloid.

00:35:20.600 It just calls into it the necessity and sufficiency of it. In other words, it could be that you have to

00:35:28.440 have, I mean, I'm making this up, but to illustrate a point within logic, it could be that you need to

00:35:34.120 have amyloid beta deposition to cause dementia, but that is not sufficient. It is only a necessary

00:35:41.160 condition and that you might need other factors to coalesce around it. The obvious example that

00:35:46.200 comes to my mind is LDL and ApoB, which is necessary for cardiovascular disease, but not alone sufficient.

00:35:52.360 You still need an inflammatory response and an immune response.

00:35:55.640 I go beyond that point. What I'm saying is against the dogma.

00:36:00.280 You're saying one step further than that. You're saying that not only is the deposition of amyloid

00:36:07.480 not correlated strongly enough, it might not even be causally related.

00:36:12.440 Not even. It is not causally related to what we call primarily Alzheimer's disease, which is this

00:36:21.000 majority of late onset. That's not true for the early onset. What I'm saying is that there are two different

00:36:28.280 diseases. The early onset, there is a role for this amyloid deposition. You can demonstrate this.

00:36:34.280 In other words, if you take autopsies of 50-year-olds that die from heart disease, cancer, or accidental

00:36:42.280 death, and you examine their brains relative to 50-year-olds who die from early onset dementia,

00:36:48.600 the relationship is more clear. Oh, it is clear.

00:36:51.640 The amyloid beta is playing a causal role. Yes, there is no question. And you can find the

00:36:56.920 genetic mutations and you can induce it in the animal, but that's not the case in the late onset.

00:37:03.320 And the neuropathologists will tell you if they don't know what the clinical picture was,

00:37:11.400 they wouldn't be able to say that this was what they refer to as a probable Alzheimer's disease.

00:37:18.520 So when they see exactly the same pathology and then there's no evidence of cognitive deterioration,

00:37:24.280 they just diagnose that brain as possible Alzheimer's disease. So this created a circular

00:37:31.000 definition. To be clear, to close the loop on that analogy with heart disease,

00:37:37.000 you would have to know that there are cases where patients have significant dementia that by all other

00:37:44.200 metrics is consistent with Alzheimer's dementia and not Lewy body or something else. And there is an

00:37:49.800 absence of amyloid beta deposition. And what percentage approximately, I know it's hard to

00:37:56.760 know these things because we don't always get autopsies, but in your experience, what percentage of

00:38:03.160 patients who die with or from Alzheimer's disease that is late onset do not have the histopathologic

00:38:12.280 features of amyloid beta? The majority of patients that are diagnosed as Alzheimer's disease,

00:38:19.480 pro-Alzheimer's disease when they die, have the same level. It's not that they don't have,

00:38:26.760 because it's an age-related deposition, the same levels of all the patients that are comparable age.

00:38:34.520 And the only reason that they are labeled Alzheimer's is because they have the dementia. The pathology

00:38:41.480 cannot really tell them apart. If you give these two pathologies blind to the medical diagnosis or

00:38:48.600 clinical examination, they won't be able to tell apart which are the ones that are actually demented

00:38:56.520 and which are not, if you do it in a match. There is a large degree of variability and pathologies are

00:39:02.920 not quantitative. Pathology is an approximation. You look at only a few sections through the cortex,

00:39:10.440 and then you give a certain proportion of the findings that are found that you see as categories. But

00:39:18.760 even when I have done this personally, in 2001, we published in the Journal of Neuroscience,

00:39:25.960 a study where we use brains from people who die from Alzheimer's. The main difference from my study,

00:39:32.520 from what's been done before, is that we were able to obtain brains with only a few hours after the

00:39:41.560 individuals had died. We call it a very small post-mortem interval. And I was able to do this

00:39:48.760 by collaborating with the Institute in Arizona. There is a city called Sun City, Arizona. And they

00:39:56.600 have a Sun City Health Center, which actually ascribes to these amyloid and neurofibular rectangle ideas.

00:40:04.200 But what we did with them was we went, we traveled there and we, my PhD student, we collected these

00:40:12.120 brains, controlled brains and brains of people who have died, die of Alzheimer's. Some of them,

00:40:17.720 we were able to collect them fresh right there. And were you and your team also blinded to the

00:40:24.040 circumstances of the death prior to the autopsies being performed? No. What we did is we collected all

00:40:31.400 the brains and they were, I sectioned them into pieces and these pieces then were frozen. And then

00:40:39.400 one sample would remain there. I see. I see. So you did everything in parallel. Yeah. It would be

00:40:45.400 chipped here to Austin. And once the samples were chipped, they were coded. But when we were there,

00:40:51.800 no, we knew when somebody died because I had a pathologist with me who had to certify.

00:40:58.120 They were dead so that we could immediately... But when the pairwise results were evaluated,

00:41:05.000 the evaluator was blind to the clinical circumstances of the patient's death? Yes. What we did in that

00:41:12.120 study was we were not only interested in just looking at amyloid plagues and neurofibular rectangles

00:41:19.400 being done. We were interested in seeing, is there any biochemical change that could account

00:41:26.760 for this so-called hypometabolism, this decrease in energy metabolism that is seen early in Alzheimer's?

00:41:36.440 Is it generally well-regarded bringing it back to some of your earlier work in PET? I assume it is

00:41:41.720 generally agreed upon that patients who are in the stages of cognitive decline have hypo-functioning

00:41:49.640 metabolism. So their PET scans show less glucose uptake in the brain. Is that generally acknowledged?

00:41:55.160 And not only FTG PET, when you do also cerebral blood flow, you find the same. When you do fMRI,

00:42:03.720 arterial spin labeling to look at blood flow, every technique that has been used has demonstrated

00:42:10.840 that first it was with mild Alzheimer's cases, but more recently also with the so-called mild cognitive

00:42:18.840 impairment. And in those cases there is hypometabolism. And the hypometabolism is primarily not in the

00:42:32.120 regions that become atrophic. Later on in the disease, like in the temporal lobe, it's primarily in the

00:42:40.120 posterior cingulate cortex. One region of the brain that is in the medial part in the center

00:42:46.680 of the brain. This area is the one that you can see having earliest sign of hypometabolism.

00:42:54.120 And from a phenotypic standpoint, what does it control in the normal brain?

00:42:59.000 This region provides the major input to what is called the entorhinal cortex, which is the part of

00:43:08.040 the temporal lobe that then feeds into the hypocampal formation. So what essentially is happening is you

00:43:17.800 have a functional disconnection between the main input to the entorhinal cortex. The entorhinal cortex

00:43:26.440 is the primary source of inputs to the hypocampal formation. So when you functionally denervate

00:43:34.760 a region in the brain, eventually that leads to atrophy from that region that is receiving the stimulus.

00:43:43.000 It is receiving that. Just like happens when you denervate a muscle in the periphery,

00:43:48.040 there is atrophic action and action that that region survives because it's being stimulated by the

00:43:54.680 other one. So people have missed, when you study pathology, you don't study these functional changes

00:44:02.600 and you don't look at the system as a network of pathways that influence functionality. You're seeing

00:44:09.320 the end result, what has happened after all of these processes are taking place over the years.

00:44:16.520 So by doing that, you cannot infer these other phenomena.

00:44:22.120 So if you take an animal like a mouse and you just take out the, it's the posterior cingulate?

00:44:27.080 The posterior cingulate.

00:44:27.960 Yeah. If you lesion that in a rat or a mouse acutely, which is not the same as what's presumably

00:44:33.800 happening in this disease state, what is the immediate phenotype of that animal or behavior?

00:44:39.880 Well, you don't have to lesion it. You can functionally deactivate it, which is more

00:44:46.040 similar to what is actually happening in Alzheimer's. It's not that this region is damaged structurally.

00:44:52.120 Right. It's just functionally not allowing the conduit.

00:44:55.000 Yeah. It's the signaling conduit.

00:44:56.440 Yeah. Affecting that network that is providing the main input to the hippocampal formation.

00:45:01.400 You get the same kind of memory deficits that are characteristics of the initial stages of

00:45:07.560 dementia. And is that because of the role the hippocampus plays in the consolidation of memory,

00:45:13.480 or is it to do more with the target in the temporal lobe?

00:45:17.240 It is because it's a network, not a single region. In other words, for example, long time ago,

00:45:25.720 in the 1930s, there was a circuit that was defined by an American neuroanatomist called James Pappes,

00:45:33.880 also pronounced Pappes. And he describes the connections between the cingulate cortex,

00:45:40.840 this parahypocampal cortex that we now primarily refer to as the entorhinal cortex,

00:45:47.160 and then from there to the hippocampal formation. From the hippocampal formation,

00:45:52.280 the main output goes to a region called the mammillary bodies. And then from the mammillary

00:45:58.040 bodies, it goes to the anterior part of the thalamus. And then from the thalamus, it fans out the

00:46:05.320 projections back into the cingulate cortex. So it creates a circle. And this is often being referred

00:46:12.200 to as the limbic circuit of papers. And we know it has to do with emotional memory formation because

00:46:20.760 events that have a large emotional signature are the ones we store.

00:46:27.640 We create the greatest memories from them.

00:46:29.640 Yes. So if you affect this system anywhere in this system, you get a memory disease and they just

00:46:38.520 have different names. So for example, people that have chronic alcohol, they develop sometimes,

00:46:46.280 it's referred to as a Wernicke's-Korsakov dementia, also known as Korsakov psychosis.

00:46:52.600 You can get this from B vitamin deficiencies as well.

00:46:55.880 B1 deficiency, thiamine deficiency in particular. You look at the pathology of the brain. Where is

00:47:02.760 the damage? The damage is primarily in the mammillary bodies. Well, the mammillary bodies is the main

00:47:09.240 output from the hippocampal formation. So whatever the hippocampal formation is contributing,

00:47:14.040 if you are knocking down his main output target, you get the same thing. Then in a second place is the

00:47:21.720 hippocampal formation itself, then the enteroendocortex and so on. All you have damage in any part of the

00:47:27.960 surgery system. There's also something called diencephalic retrograde amnesia that happens with

00:47:33.880 thalamic lesions. Well, this is when these lesions interfere with these anterior thalamic areas. So really,

00:47:41.240 in order for us to see the memory problems that we have linked usually with Alzheimer's dementia,

00:47:48.520 you have to engage this system because that system is part of the brain regions in which this is

00:47:55.000 operating. You use the term retrograde there. For the listener, we should explain the difference

00:47:59.480 between retrograde and antegrade amnesia. I'll let you do that quickly. But of course, my follow-up

00:48:04.520 question will be, in the earliest stages of dementia, is the bigger issue the inability to

00:48:10.520 form new short-term memories, which would be a form of antegrade amnesia? That would happen before the

00:48:15.800 retrograde amnesia, which is later. Yes. Let me explain. In the early Alzheimer's disease,

00:48:21.080 the main problem is not in this limbic circuit. When that happens is when you can see the hypometabolism.

00:48:30.200 That's when you can see the behavioral changes in the individual as well. But before that,

00:48:36.040 in the prefrontal cortex, especially the lateral, we call dorsolateral prefrontal cortex,

00:48:42.760 you have a functional deficit that is interfering with what we call working memory. So you can think

00:48:51.960 of memories as having three modes or temporal stages, an immediate memory mode where you can remember

00:49:00.760 things for only a few seconds. Tell me your phone number and I have to write it down. That's correct.

00:49:05.720 That's the perfect example. A clinician will do this by giving a string of numbers to people,

00:49:12.920 and people will be able to remember approximately seven numbers. So it is usually seven plus or minus two

00:49:23.640 items. And this is the reason why the telephone numbers have seven digits, because most people,

00:49:30.360 after reading seven digits, turning around to try to punch those numbers in the phone, if there are more

00:49:37.000 than seven, they drop, some of them. This is this immediate memory mode. But for memories to happen,

00:49:44.520 they have to move from this immediate memory mode to a more recent memory mode. So the immediate,

00:49:49.880 that movement from immediate to recent is done by this prefrontal cortex. So the initial deficit that

00:49:56.440 you see in Alzheimer's and all of these types of dementia of all age is in this more immediate memory

00:50:04.120 memory mode. And one way we refer to this is also working memory. So for example, you come out of your

00:50:10.440 house and you lock the door. But after a few seconds, you're working to your car. Then you ask, did I lock

00:50:18.040 the door or is it unlocked? And then you have to go back and check. So this is the first thing that you're

00:50:26.840 going to have. And it happens physiologically as a function of aging. And this is the first one,

00:50:32.040 these working memory things are. So the prefrontal one is the initial signal that there is a memory

00:50:39.320 problem. This is before. And this is an anti-grade memory. In other words, it's a new memory that you

00:50:45.880 want to form. So this is the first thing that is affected. But once the memory are in the recent memory

00:50:51.800 mode, this, for example, would be your phone number, which is one of the easy seven digits to remember because

00:50:57.480 you're so familiar with it that it's now become quote unquote permanent memory.

00:51:01.080 By repetition, by exposure to the same items, this reverberate in that limbic circuit that I just

00:51:08.120 told you. And the hippocampal formation has an inner circuit that is crucial for that. So it is crucial

00:51:15.320 for that forming. And then you being able to retrieve that number again. So when that circuit becomes

00:51:22.360 engaged at any point, then you start having this retrograde memory problem. You cannot remember

00:51:28.120 your number. Which is interesting. That's the point at which the family members tend to really

00:51:33.720 notice what's happening and become concerned. Yes.

00:51:36.360 But the patients tend to become concerned much sooner. The patients become concerned

00:51:41.560 with the anti-grade memory deficits. You're absolutely right.

00:51:45.320 How do you distinguish between something you said a moment ago, which was this slight deficit

00:51:51.320 of formation of new memory is on some levels, not necessarily a pathological finding as we age,

00:51:57.960 but how do we differentiate between the pathologic or the appropriate age related versus the potentially,

00:52:05.000 you know, the harbinger of something pathologic?

00:52:06.840 It is difficult to draw the line. This is one of the main reasons that this diagnosis of mild

00:52:12.920 cognitive impairment has been elusive. I have asked this question to all the researchers

00:52:19.640 and I get very many different opinions. And the main reason is that the only way to know for sure

00:52:25.560 is to compare this to your own history, to compare it to yourself. So in this case, the patient and their

00:52:33.160 immediate patterns, they are more knowledgeable whether there being a change. If you just compare to

00:52:41.160 a standardized age population, you may not see any difference, but the patient will tell you,

00:52:48.280 no, I know I am having more difficulty with, for example, this working memory task.

00:52:54.200 So it is a challenge. But the beauty of this is you don't have to wait because everybody goes

00:53:01.960 through this cognitive decline. It's just to a different extent. And we all start out at a different

00:53:08.360 level of cognitive performance. So it's very difficult to have a standard. So my approach

00:53:15.560 is to try to intervene at that point. And therefore, the main target at that point is to intervene

00:53:22.600 in the prefrontal cortex, the region that is just behind your forehead. And that one engages,

00:53:30.360 we call it a central executive network that for cognitive processing that is involving working

00:53:38.040 memory, that is involving problem solving, that is involving sustained attention, vigilance.

00:53:44.120 Those are the things that you're going to be seeing first, having a decline as you grow older,

00:53:50.920 just like all kinds of tissues decline as you grow older. This is a reality.

00:53:57.240 But it is possible to intervene then before you get into the limbic system problems. And that's

00:54:03.880 the approach that we have done and in our interventions. And I think this is what's

00:54:09.240 going to make the biggest difference. So let's go back to now the sort of revised hypothesis. If I can

00:54:15.400 summarize, the actual nomenclature of Alzheimer's disease might be a bit of an unfortunate artifact in

00:54:21.880 that it was first observed in a subset of what would become this disease that really isn't

00:54:27.880 representative of the epidemic that we're seeing today. Absolutely right.

00:54:32.280 And so we'll put that aside for a moment because despite how tragic those early onset cases are,

00:54:38.040 and they strike me as among the most tragic things I've ever seen in medicine, by the way,

00:54:42.600 you have more experience with this. The thing that's running amok right now

00:54:46.440 now is this sort of late onset dementia that it seems to me that we are probably diagnosing it

00:54:54.520 much more than we were before, but it also seems to be increasing out beyond just the rate of

00:54:59.800 diagnosis. And it also seems to be increasing at a rate disproportionate to the increase in our

00:55:05.000 longevity, which is really not that significant. I believe that human longevity

00:55:09.000 longevity is increasing at about 0.4% per year in the United States. And yet the rate of

00:55:16.520 growth of Alzheimer's disease is growing much more than that. So if you discount that somewhat for the

00:55:21.880 rate of, for the diagnostic acumen or urgency with which we seek it, there's still a gap,

00:55:26.920 which means on a real level, not just a perceived level, this disease is becoming more common.

00:55:32.840 In your research, you talk about five areas of study that help you think about this. The

00:55:38.360 epidemiology of the disease, the imaging of the disease, the pharmacologic response to the

00:55:44.280 disease, the pathologic findings in the disease, and then the clinical course of the disease. You

00:55:51.000 and your colleagues have a different hypothesis that pertains to the vascular system. Yes. This is

00:55:56.760 actually the original hypothesis that was associated with senile dementia. I don't want to take credit for

00:56:04.760 for the people who have gone after that because in the early days it was just an idea, not well

00:56:10.520 formulated. But what seems to be happening is if you compromise circulation to the brain, you're

00:56:18.920 always going to get a neurological deficit. However, in the case of what we're seeing as late onset

00:56:25.160 dementia that I may refer to as features dementia as opposed to the early onset Alzheimer's dementia,

00:56:33.480 which is what should have been named, there is a chronic hyperperfusion. That is, the brain is

00:56:40.120 receiving less blood supply. And for example, it is known that between 22 years old to 60 years old,

00:56:51.080 there is a decrease of about 20 percent on your supply of blood to the brain. So some people have

00:56:58.680 calculated about approximately half of a percentage per year in statistical terms.

00:57:04.200 Do we have a sense of why? How much of that? I mean, because I think a lay person might understandably

00:57:10.760 but naively assume that is just due to a gradual and gradual narrowing of arteries or something like

00:57:17.000 that. But it strikes me that that's very unlikely the case and that it's much more related to something

00:57:22.920 within capillaries and or other metrics. Because paradoxically, as we age, we're seeing an increase

00:57:29.640 in our blood pressure typically. So when you're 20 versus 60, you're generally running with a higher

00:57:34.280 blood pressure. So if anything, you would think that should increase cerebral perfusion, not decrease

00:57:38.840 it. But of course, we're not seeing that. So what do you think at the level of vascular biology would

00:57:44.520 explain even that observation? Yes. Unfortunately, the answer is all of the above. In other words,

00:57:50.200 the vascular changes happen at the microscopic and microscopic levels. But it is the case if you,

00:57:57.960 for example, only look like we have done, for example, the carotid artery, the one in the neck

00:58:04.440 that supplies the blood to the head, this is where most of the blood is going to the brain from this.

00:58:11.160 And you can use ultrasound imaging non-invasively and are able to look at the layers. So even the

00:58:18.440 intimal thickening of the carotid artery, which would presumably get a little more and more and

00:58:23.640 more as one ages, is going to play a role in this potentially. Oh yes. There is a linear relationship

00:58:30.280 between what we call the intima media thickness, the layers of the artery and the decline in

00:58:38.920 cognitive function. Now why, I mean, this sounds silly, but why a linear relationship given that it

00:58:44.600 should be non-linear, shouldn't it? Given that with increase in intimal thickening,

00:58:49.960 you would see exponential change in diameter or in cross-sectional area. Wouldn't that lead

00:58:56.760 to a non-linear change in perfusion? No. Which I realize you were talking

00:59:01.000 about cognition, not perfusion. Cognition, not perfusion.

00:59:03.800 The reason there is not a linear change with perfusion is what you alluded to. We have an

00:59:09.800 auto-regulatory mechanism. I get it. That basically can start to auto-correct, at least

00:59:15.560 try to dampen it, dampens it from an exponential problem to a linear problem. That's a beautiful,

00:59:21.800 beautiful example of biology. So has the artery become stiffer with the thicker walls? It's just

00:59:28.120 like if you imagine somebody having a hose that is releasing water and then you stick your finger in

00:59:34.360 front of the hose and you can see how the water is coming in a faster place. So this is one aspect,

00:59:41.400 but this is the auto-regulation. The body is trying to achieve that. It does that when the walls become

00:59:48.200 stiffer because of the thickening. When you have this systolic pump that they're supposed to comply,

00:59:54.840 no arterial compliance, they don't do that. So even though you may see the lumen being the same size,

01:00:01.320 in other words, the hole being the same size, but it's not the same size when you have the pulse,

01:00:07.480 the bolus of blood going through that it has to open up. However, when we increase blood pressure,

01:00:14.440 we have a constant process of trying to increase blood pressure to maintain that same level of perfusion.

01:00:21.480 So the compensation for the macrovascular disease may actually be driving part of the damage at the

01:00:34.440 microvascular disease. Yeah. You're pushing now with a higher blood pressure through capillaries,

01:00:39.960 and this creates a pathology at this boundary we call the endothelial walls. And these endothelial walls

01:00:47.000 are now subjected to mechanical pressures that they were not designed to do. And you have extravasation,

01:00:54.520 and you have cells that normally are only engaged when we have like a hemorrhage, like the platelets

01:01:01.880 to try to coagulate. Now they start sticking to these endothelial walls and compromising some of the

01:01:08.840 microcirculation as a consequence. So the auto-regulation cannot compensate and it creates

01:01:18.040 additional problems as time goes by. And that's why you are actually better off with less blood pressure

01:01:25.880 by controlling your high blood pressure than with more, even though you're trying to make up for

01:01:32.120 the decreased blood supply. And this has actually been borne out in very recent clinical trials. Every

01:01:37.400 five years or so, we see more and more data revising how we think about blood pressure regulation.

01:01:44.040 And the most recent results seem to indicate the best outcomes occur with a systolic blood pressure

01:01:50.440 below 120 millimeters per mercury, a diastolic below 80. Formerly, this used to be 135-ish,

01:01:58.600 over 90 was accepted. So that's a significant difference because many people walk around,

01:02:05.560 many adults walk around with a blood pressure above 120 over 80.

01:02:08.920 You're right. And that is an index of this pathology that is developing in the large arteries,

01:02:16.840 like in the carotid here. But I'm using the carotid as an example. When this happens at the level of

01:02:21.720 the carotid... You know it's happening up to vertebral arteries and into the circle of Willis and the main...

01:02:27.880 Basically, it's happening more in the arteries that have the largest flow, because we get like about

01:02:34.520 one-third of the blood going into the head, primarily for the brain function. So there is a much more

01:02:42.360 blood flow that is going through those arteries than the one, for example, going through your arm,

01:02:48.200 your brachial artery. However, in the case of the heart, the same thing happens. You have the small

01:02:53.960 coronary arteries that are feeding the heart itself as soon as it pumps. So they have greater flows.

01:03:01.800 And the other thing that happens, these walls are not only thicker, but they become irregular,

01:03:07.640 especially the inner walls are no longer smooth. And when they're no longer smooth, you start creating

01:03:15.480 turbulence. That is, if you look at the flow of liquid, when they hit an irregularity in the

01:03:22.360 walls, there is a little turbulence. So this turbulence creates a system in which deposition

01:03:29.080 is going to be favored, like when blood is going. Or in the blood, it's usually the white blood cells.

01:03:36.840 Is it usually a macrophage that infiltrates as well?

01:03:39.480 Yes. But even before infiltrating, they identify this area of turbulence as an area of injury.

01:03:46.840 And they start aggregating there. And because of the turbulent cells, they start then dying out

01:03:54.520 against the walls. And unfortunately, cholesterol levels then can add to it. But they are not the

01:04:02.200 problem. The high total cholesterol is not the reason. Again, they're confusing causality here

01:04:09.960 with a consequence of this problem. So lowering your total cholesterol is not going to really

01:04:16.520 make a major difference in this progression, which is, I think, one of the biggest misconceptions

01:04:22.840 that is happening in medicine right now. But in any case, you have a number of phenomena that are

01:04:29.480 taking place that are contributing to the vascular hypoperfusion. On the other hand,

01:04:36.360 you can have a similar type of insult to the brain not coming from this atherosclerotic process.

01:04:44.840 If the heart muscle itself is compromised in its function because of a process where it weakens

01:04:52.600 its ability to operate as a pump, you're going to have hypoperfusion that is going to be developing.

01:05:00.040 And in that case, there would even be less likely that you're going to have an

01:05:03.720 auto-regulatory mechanism for that. So you can have heart disease that is affecting the pumping,

01:05:11.080 you know, the force of the pump that can lead to the hypoperfusion. You can have arterial disease

01:05:18.520 like arteriosclerosis that is causing similar kind of phenomenon with some more complications

01:05:24.600 that are detected by this high blood pressure. In the cardiac case, you will not see the high blood

01:05:30.040 pressure, but in the other one, you will see that. And so all of these things can be detected.

01:05:35.160 It is possible for cardiologists to advance and measure these things. And once you detect this,

01:05:42.040 the health of the heart and the arterial circulation in particular is very closely related to the health

01:05:49.400 of the brain. So if whatever you do that improves cardiovascular health will also help the brain.

01:05:57.480 But there are some differences. For example, the brain in some ways seems a little bit more exposed

01:06:03.800 because the brain is perfused during systole at a higher pressure. The heart is the only organ that

01:06:11.320 is actually perfused during diastole. So in that sense, the coronary arteries themselves are less

01:06:18.600 susceptible to hypertension than the arteries in the brain or the kidney for that matter, which would be the

01:06:23.960 two organs that seem to be most damaged by hypertension, more so than the heart.

01:06:28.680 Yes.

01:06:29.160 The other thing that I'm hearing you say that creates a bit of a differentiation between the heart is,

01:06:35.480 you know, in the process of atherosclerosis in the heart, cholesterol does play a very important role.

01:06:40.680 But so you still have the initiation of the endothelial injury, which is necessary.

01:06:46.040 But once the lipoprotein can get inside the subendothelial space and becomes oxidized,

01:06:51.240 that's what elicits the immune response, which is what does the damage. What you're describing

01:06:55.960 in the brain is two different processes, if I'm hearing you correctly. The first is

01:07:00.200 cerebrovascular disease that leads to strokes, occlusive or hemorrhagic, which that's a separate

01:07:07.640 disease because it tends to produce an acute event that is the result of an acute hypoperfusion

01:07:14.280 that usually produces a much more functional deficit. So it's almost like you can think of

01:07:18.440 that as a quote unquote brain attack, the way we think of a heart attack.

01:07:21.560 Correct.

01:07:22.360 But what you're describing that is now sort of unique to me is a different type of much more

01:07:28.520 indolent chronic hypoperfusion that actually seems to have a slightly different pathophysiology

01:07:33.960 from coronary physiology that doesn't produce an acute event, but rather a chronic disease.

01:07:40.040 Is that, am I, did I summarize that?

01:07:41.720 You summarize that really well. It is this chronic brain hypoperfusion, regardless of the

01:07:48.360 particular cardiovascular cause, because I told you with heart failure, you can have,

01:07:54.680 you can simulate that aspect, but without some of the other components.

01:07:58.360 Right.

01:07:58.840 So it is possible nowadays to pick this up and to intervene, to try to resolve these vascular

01:08:06.920 problems or cardiovascular, they involve the heart.

01:08:10.440 So the epidemiology states the first and most obvious relationship, which is so obvious that

01:08:16.440 it's not almost not helpful, which is there is no greater association with Alzheimer's disease than

01:08:21.320 age, just as there is no greater association with cardiovascular disease than age. So that's stating

01:08:28.120 the obvious, but it's very difficult to draw a clear hypothesis or at least confirm a hypothesis.

01:08:34.600 So the next layer of thinking on the epidemiology is what? Is it the association with hypertension

01:08:41.560 or is it the association with cardiometabolic disease? How do you then continue down that

01:08:47.240 line of thinking on from just, just again, before we get to the more interesting stuff,

01:08:50.920 which I think is the pathology and the pharmacology, just based on the epidemiology,

01:08:54.760 what else can you infer?

01:08:55.800 What would be ideal to me would be what is the main purpose of that circulation from the point

01:09:04.120 of view of energy is to bring oxygen to the tissue, tissue oxygenation. It is only through this process

01:09:14.200 of reducing oxygen to water that in mitochondria, this process is linked,

01:09:23.080 the cellular respiration is linked to the production of chemical energy.

01:09:27.720 So the more direct measurements would be measurements of oxygen consumption,

01:09:33.880 but also could be the enzyme that is responsible for that oxygen consumption.

01:09:40.680 And that's where it comes to our work. And what we found in the brains of those Alzheimer's patients,

01:09:46.040 we found that the enzyme calls cytochrome oxidase or cytochrome C oxidase.

01:09:50.680 Which is complex four in the electron transport chain.

01:09:53.640 The electron transport is the, the last rate, the last and the rate limiting enzyme

01:09:58.920 and the one that actually reduces oxygen to water that is linked to oxidative phosphorylation,

01:10:06.280 the creation of ATP.

01:10:07.880 Let's pause for a moment to make sure people understand this. It's

01:10:10.680 so important that even though I think I've talked about this before, it's worth reiterating.

01:10:15.160 The mitochondria has an inner and outer membrane, and these have four complexes. Three of them span

01:10:21.480 both the inner and outer membrane. I believe it's one, three, and four. Complex two is only on the inner

01:10:26.120 membrane. These things are about the most essential elements of life. Interrupting their activity for

01:10:33.320 even moments at a time is the end of life.

01:10:36.120 I would say it's the key to aerobic life on the planet.

01:10:40.520 Yeah. You can't overstate the importance of the electron transport chain.

01:10:46.520 As you pointed out, it is basically, you know, we can't create energy out of nothing. We simply

01:10:52.440 change its form. And so when we eat food, we're eating stored potential energy that is in a chemical

01:10:58.920 form that is generally between the carbon-carbon, carbon-hydrogen bonds. As these things get reduced

01:11:04.520 to simpler and simpler molecules, this process specifically within the mitochondria takes

01:11:11.560 these units and it, by breaking apart the chemical bonds, creates an electrical gradient by shuttling

01:11:19.880 electrons outside of this membrane as they go from complex one, two, three. And of course, they each

01:11:24.760 come with their own reducing agents. I spend my most time thinking about complex one, which is the NADH,

01:11:29.960 NAD shuttle. But I believe complex four is NADPH, isn't it? Is that what it's using as the electron

01:11:35.240 acceptor donor? Yes. I need to emphasize from what you're saying so people understand. The whole purpose

01:11:41.800 of that chemistry that is done with the foods that we eat is to generate electron donors. Electron donors

01:11:49.800 are going to donate their electrons to the electron transport. And there are only two of them,

01:11:56.440 the NADH and the FADH. And the NADH primarily, it donates to different parts of the electron

01:12:05.320 transport systems, but the other one, the FADH only to complex two. So you have like two entry points,

01:12:12.040 complex one and two, and then... And that's why complex two doesn't span the full membrane. It's

01:12:16.760 sort of sitting there only on the internal. And it's much smaller than complex one is the largest one.

01:12:20.920 So this is a key. This is a biochemical key to this phenomenon because what we eat from an energy

01:12:27.800 point of view is just becoming electron donors. So it's, can we donate electrons to the electron

01:12:33.800 transport? If we could do that, we can accelerate respiration because the ultimate electron as sector

01:12:40.760 in nature is oxygen. And that's what we call oxidation, the process of removing electrons.

01:12:46.040 And so making water out of oxygen and these protons that are being donated is the ultimate

01:12:54.760 byproduct of respiration. That's why we breathe out water vapor. And of course, all of this is in

01:13:00.440 service of creating an electron gradient to then fuel the generation of adenosine triphosphate ATP.

01:13:08.440 Yes, what the mitochondria have done is coupling this affinity of oxygen to take these electrons that are

01:13:16.680 coming from the food that we eat into a closed system in which the electrons, when they are moving from

01:13:28.920 one complex to the other, they are releasing what is called a proton that is positively charged. And this

01:13:37.320 is trapped in that intermembrane between the two membranes that you mentioned, the outer and the inner

01:13:41.880 one. And the matrix of the mitochondria, the more innermost portion is primarily negative in electrical

01:13:52.200 charge. Ions are negative. So these protons are trying to move. They are attracted towards this

01:14:01.640 negativity, just like when you have the poles in a magnet, the positive and the negative poles. This

01:14:07.880 is what we call electromotive force. There are only very few forces in nature, like gravitation,

01:14:14.280 and this one is electromotive force. So the system was designed in such a way that the protons will

01:14:20.280 leak through a hole. And that hole or pore is this complex five. And complex five is designed so that when

01:14:30.360 the proton is pushing through to get from the inner, excuse me, from the inter membrane space to the

01:14:39.480 matrix, it clicks, changes the conformation of that enzyme. And that movement generates the energy for

01:14:48.760 a phosphate to be bound to ADP. And that phosphate is called inorganic phosphate. When this is what in

01:14:56.120 chemistry is called an endothermic reaction, it needs energy in order to happen. And it's because of

01:15:02.680 that movement. And then later on, when you need some other enzyme to work, all of these chemical

01:15:09.880 reactions that have to do with life are catalyzed or mediated by enzymes. What this means is that

01:15:16.120 you may have the reactants already in place, but nothing is going to happen in terms of products,

01:15:22.200 unless you provide energy to the system. So these are so-called reactions that when you remove that

01:15:30.440 phosphate from the ATP, it generates heat. And this is what we call calorie. And you can then have a

01:15:40.200 relationship, a quantitative relationship with how much food you eat, how many electrons are donated,

01:15:45.800 how many of these phosphates can be broken and generate that heat. And that heat is just like in

01:15:51.160 chemistry, when you add your reactants in a beaker and you have a catalyst and nothing was happening.

01:15:57.560 And then you apply heat and then all the resulting reaction happens, it changes color, for example.

01:16:03.000 And when that phenomenon happens, then we call that an exothermic reaction that break it and it fuels.

01:16:12.200 So the key to the system is to be able, how can we facilitate that mitochondrial respiration?

01:16:18.120 And this illustrates, of course, the most important point here. What you're saying is

01:16:23.400 the whole purpose of eating is to convert chemical energy into chemical energy from one form to another.

01:16:29.480 But to do it, you need an intermediary to translate. And that intermediate has to turn the chemical energy

01:16:35.720 into electrical energy that then facilitates a conversion back to chemical energy. That is the key

01:16:41.240 to life. Yes. And that is what the mitochondria do. However, there is a way, at least aerobically,

01:16:46.760 we can obviously do this inefficiently and anaerobically later, but yeah. Correct. Correct. You can do this,

01:16:52.520 especially in other tissues, not so much the brain. You can generate ATP without using oxygen and this machinery.

01:17:00.520 But every organism, including single cells on the planet that uses oxygen to obtain energy relies

01:17:08.680 on cytochrome oxidase. They may not have mitochondria, but at least they need cytochrome

01:17:13.480 oxygen. Wait, I didn't realize that. So red blood cells, for example, don't have mitochondria. Do they

01:17:17.560 have cytochrome oxidase? Yes. Yes. I didn't know that. Yes. If they use oxygen to generate ATP,

01:17:24.760 they have to have cytochrome C and cytochrome C oxidase. This is the minimum requirement. That's why

01:17:32.280 you can look at cell lines from microbes and so on, and you can identify these proteins. As long as it's

01:17:39.000 aerobic, it's the only way nature found how to solve this. But the interesting thing is that when the

01:17:46.760 circulation is compromised, then you have less oxygen. You're creating a situation where these

01:17:53.080 events cannot move on. It doesn't matter how much you eat, and this is happening in older people, 1.00

01:17:59.000 it doesn't matter how much they eat. In fact, their brain is telling them that they should be hungry

01:18:04.360 because they are not able to transfer those electron donors into electron transport and produce energy.

01:18:11.800 So they feel they're energy deprived. So they increase food consumption, especially they are attracted to

01:18:17.960 carbohydrates. Simple carbohydrates that can quickly break down and produce these electron donors.

01:18:23.320 So do you think that this is the first insult then? Because you talked about this slightly

01:18:29.000 different type of microvascular disease that is much more chronic and insidious and doesn't lead to

01:18:33.720 acute changes like hemorrhage or occlusion. How does that change ultimately impact the ability of the

01:18:41.880 mitochondria to do its job and facilitate electron transfer? Yes, you put your finger on it. This is

01:18:48.440 what links this phenomena. Regardless of whether the chronic hyperperfusion or the more acute,

01:18:54.360 one of the things that happen is when we have a hypoxia situation, cytochromoxidase is an inducible

01:19:02.440 enzyme. What that means is that our body only maintains

01:19:07.640 as much as it's needed, as much as it's demanded. It's a complex of 13 different subunits,

01:19:14.440 three of them mitochondrial DNA derived and the other 10 from nuclear DNA. And you can regulate it

01:19:21.240 at many different levels, including both the nucleus or mitochondria. But essentially, within minutes,

01:19:28.600 if, for example, you have an area of ischemia, you occlude the blood vessel,

01:19:32.600 half an hour later, you lost a significant amount of cytochromoxidase from being functional.

01:19:38.360 And that's irreversible then? No, it is not irreversible. That's the the advantage of the

01:19:44.200 system. The system works on demand. It may not be immediately reversible, depends on on the level

01:19:50.760 of regulation. In other words, you can simply inhibit the enzyme and the enzyme is still there.

01:19:56.440 Or you can disassemble the catalytic units of the enzyme, the ones from mitochondrial origin,

01:20:03.640 and then you have a partial enzyme, not the so-called hollow enzyme. Or you can eliminate

01:20:10.120 the other components. And throughout the mitochondrial inner membrane, you have all of these gradations

01:20:15.720 of stages that can be used for regulating this. So you can regulate it in a more immediate way,

01:20:20.520 or eventually you need proteins transported from the cytoplasm to be chipped where the mitochondria are

01:20:29.320 and incorporated into this. Why was this done? Because mitochondria have a symbiotic relationship

01:20:36.920 with the cells that they live on. And this was created to develop a dependency that mitochondria are

01:20:44.840 doing this, but they cannot do it on their own. The cell has found a way to obtain the energy,

01:20:52.360 but it's conditional on then contributing a component that is necessary for the entire machinery to work.

01:21:00.040 The important portion here is that these phenomena are coupled. As soon as you have hypoxia,

01:21:06.680 ischemia you reduce, then this machinery goes down-regulated. Is that true of complex one,

01:21:13.320 two, three as well? Are they also inducible the way complex four is? Not as much as complex four.

01:21:19.400 They are, to a certain degree, if you keep taxing the system, it's going to happen. But the one that has

01:21:25.320 the more flexibility from more immediate to long term, because of this role as rate limiting,

01:21:32.360 is complex four. And that's the reason it is preferred modulator of the system.

01:21:38.200 That's why I love doing these podcasts. Every single podcast, I get to learn something new in

01:21:43.000 biology that I didn't know. I had no idea that complex four was inducible to a greater extent than

01:21:49.800 the others. As it is, for example, you may have heard for sure during your training about other

01:21:56.520 inducible enzymes, the cytochrome systems in the liver. P450, the most inducible of them all.

01:22:04.840 So it's a perfect example. If you drink more alcohol, you're going to build up more of these

01:22:11.320 cytochrome enzymes. So these are the most inducible enzymatic complexes that we have.

01:22:16.120 Just never think of it in something so important. Not that the liver is less important, of course,

01:22:20.680 but the ETC is so fundamental for everything that we do. It's so interesting to think of that.

01:22:28.200 And it's also interesting to hear you say that at least in transient periods of ischemia,

01:22:32.200 this is not irreversible. No, it's not irreversible. It's an inducible system,

01:22:36.120 just like you stop drinking alcohol. These enzymes are going to be down-regulated,

01:22:42.200 but if you start challenging the system again, they are inducible. They're going to go back.

01:22:47.400 Of course, you're going to suffer somewhat in between because at the beginning, you're not

01:22:51.640 going to be able to meet the demand, but they are inducible. And this is the key that I have

01:22:58.280 understood from our investigation of the Alzheimer's brain. In those fresh frozen Alzheimer's brain,

01:23:04.760 the main problem was cytochrome oxidase inhibition. The levels of the protein levels of the enzymes were

01:23:12.280 not compromised, but you could see that the enzyme was not in its catalytic functional state. And you

01:23:20.120 could demonstrate this doing enzyme histochemistry. If you were able to extract at the moment those

01:23:26.920 patients died their cells in culture, and now they're perfused, would they have still been hypo

01:23:34.840 functioning? In other words, would you still have been able to measure a deficit of oxygen utilization?

01:23:39.160 Yes. Yes. And this has been done. Groups have taken, actually what they've taken is mitochondria,

01:23:46.040 and they can then see that these mitochondrias are not performing this cellular respiration from

01:23:52.360 Alzheimer's patients. Give me a sense of what is the magnitude of the deficit to result in the

01:23:58.200 phenotype that we observe clinically? Yes. This is a very good question because if you inhibit

01:24:04.040 cytochrome oxidase, after about 40% in an organism, the organism dies. You cannot cut. This is as a...

01:24:15.560 But presumably it's a nomogram of duration and degree of suppression, right? So maybe you could

01:24:20.280 have a 40% reduction for two seconds, but not a 40% reduction for two minutes or something.

01:24:26.760 I mean, I assume that there's... That's correct. That's correct. For example,

01:24:29.800 the classic poison, cyanide. Cyanide. Okay. What does cyanide do? Cyanide is complex for a

01:24:38.040 cytochrome oxidase inhibitor. It gets into the circulation, it inhibits cytochrome oxidase,

01:24:44.280 and minutes later you die. So if that happens, it's not compatible to life. However, you can have many

01:24:52.360 degrees of this reduction because the enzyme is so inducible, you not only change the catalytic

01:24:59.080 activity of a particular... In other words, cyanide is not binary in its ability to kill.

01:25:04.040 It seems functionally binary because it's so potent that even a trace amount of cyanide will

01:25:09.000 kill. But presumably, if you dilute it enough and enough and enough, you could give enough

01:25:12.760 cyanide to somebody that they have a chronic illness due to... It's almost like it's a thought

01:25:17.640 experiment. You could induce Alzheimer's at a low enough dose of cyanide to create a functional

01:25:23.560 hypoperfusion by inhibiting complex four without killing the organism. And we did this. I like when

01:25:29.240 I think of things 10 years after someone else did it. This thought experiment was done. And in fact,

01:25:34.120 Dr. Jack De La Torre, the one that wrote the book, Alzheimer's Turning Point, that I highly recommend.

01:25:40.840 Yeah. We'll link to that for sure. And we collaborated in that study. So it works both ways. In other

01:25:46.920 words, if you compromise the circulation by partially occluding blood vessels to the brain,

01:25:53.560 you get a downregulation of cytochromoxidase, and therefore, mitochondrial respiration and

01:25:58.840 ATP production and so on. And the animals show a cognitive picture that is analogous. It's not the

01:26:05.800 same, but it's analogous to what you see in cognitive, neurocognitive disorders. And the other way

01:26:12.840 around, you can directly suppress the electron transport. And in our study, we decided to use

01:26:19.560 sodium acide because it's less potent than cyanide. And when you do that, yes, you have an animal that

01:26:27.480 at a very low level of decreasing, you can decrease up to 30% without seeing any neurological

01:26:35.720 evidence change. The animals appear to be eating and behaving normally. But when you test them with

01:26:41.960 cognitive memory tests, they cannot perform well. In other words, a 30% reduction in the oxidative

01:26:49.080 capacity of complex four shows cognitive impairment when challenged, even though behaviorally at the

01:26:56.520 gross motor level, the animal is still fine. Just like an Alzheimer's patient that you will appear,

01:27:02.280 they will appear to be generally okay. Until you test the system harder. Yes.

01:27:06.840 Yes. So these animals, and in fact, that was proposed as a model for Alzheimer's disease,

01:27:11.960 that very same approach by colleagues of mine. The one that comes to mind is Rose Bennett,

01:27:18.200 Rose and Bennett. However, because of the influence of these amyloid and tangles hypothesis, 0.85

01:27:24.760 all of these models were based on biochemical and physiological phenomena were really not developed

01:27:31.400 fully. All the attention was in the genes and the normal proteins. But yes, you can do this in

01:27:39.000 animals. You can test these hypotheses in animals. And does this lead to any change in the amount,

01:27:45.400 let's assume you had an animal model where you could do this for a long enough period of time before

01:27:49.000 the animal would die. And you had a control animal in which it was, you were not doing this. Would you,

01:27:54.760 in those two situations side by side, see a difference in amyloid beta accumulation?

01:27:59.080 No. The amyloid beta will not be a good reflection of these processes. The amyloid beta is primarily

01:28:07.000 a process that is compensatory when the cells are showing atrophy. So when cells start showing signs

01:28:14.040 of atrophy, we have a lot of amyloid beta that is released embryonically during the development of

01:28:20.840 the nervous system. And it's because during development of the nervous system, you have

01:28:25.880 phases of a large proliferation of neurons, but then you have other phases of trimming where there is

01:28:34.200 a lot of neuronal death. And in those situations that you see amyloid that is formed. So as you know,

01:28:43.560 probably the major signal for a cell to die in an aerobic organism is for the mitochondria to release

01:28:54.120 cytochrome C. Cytochrome C is the protein that carries the electron to cytochrome C oxidase. If

01:29:00.920 that machinery is not working and cytochrome C leaks out, we say the mitochondrial permeability

01:29:08.040 pore has been modified so that small cytochrome C leaks out. That's a big signal for apoptosis.

01:29:15.320 Apoptosis or programmed cell death. In other words, if a cell mitochondria...

01:29:19.880 That's the surrender of the cell. That's the white flag. Here's my cytochrome C.

01:29:23.960 So what I'm telling you is if you compromise the system, you're going to have neurodegeneration.

01:29:29.720 You're going to have cell death. And not just in the nervous system. It just happens that there

01:29:33.960 is more critical because in all the systems, we have all the ways to get ATP. But in neurons,

01:29:39.560 we don't have any significant amount of alternative ways to get it.

01:29:43.320 Yeah. That's exactly the point I was going to make is we're having this discussion

01:29:47.320 and it would be easy for a moment to say, wow, why is this all isolated to the brain? It's not. It's

01:29:53.000 just the brain, I think, has two problems. The first, you know, if you're going to be critical of

01:29:58.760 the brain, the first is an energetic problem, which is, it is simply the most demanding and

01:30:04.760 therefore it is the most susceptible to a reduction in total available energy. The brain weighs about

01:30:11.160 2% of our body weight and yet consumes about 20% of our total energy expenditure. So that's a

01:30:17.800 grossly disproportionate amount of energy. And the second, by the way, would be the kidney,

01:30:22.920 which by the way, is the second organ we tend to see great ischemic. When we see hypoperfusion

01:30:29.320 clinically, we see kidney damage and myocardial damage. So the more energy demanding the organ,

01:30:35.080 the bigger the problem. And then the second issue with the brain is this seemingly over-reliance on

01:30:40.680 oxidative phosphorylation without an anaerobic escape route. Yes, you are right on target. And this is

01:30:47.160 what makes it so vulnerable. And this is why we see these changes more as cognitive deficit

01:30:54.360 before all the tissues are really damaged or the brain itself. But as you continue with this process,

01:31:00.440 as we just talked about, if downregulation of cytochromal oxidase reaches a certain level,

01:31:06.520 cytochrome C is going to start releasing. There is this permeability change goes out and cells start

01:31:12.920 dying. So it is the the direction of causality is completely different from the amyloid ideas that 1.00

01:31:20.760 the amyloid comes there because of the gene that is abnormal. And then it's creating these cascades 0.96

01:31:26.840 that are leading to these changes. No, what we have is these problems with supply of oxygen

01:31:34.040 that happen to the brain and it's high energetic demand. And they could be due to the circulation

01:31:40.920 or it could be due to a cardiac effect on the circulation. But unfortunately, the vascular

01:31:47.640 hypothesis of dementia is not exclusionary because you can have toxic insults that affect the mitochondria

01:31:56.440 that will, for all physiological purposes, will do something similar to these cardiovascular insults.

01:32:04.200 In other words, they're going to lead also to downregulation of cytochromal oxidase and your

01:32:09.560 inability to use oxygen to generate energy. So that's why I have used that entry point into

01:32:17.320 the system because it is completely consistent with the vascular hypothesis of dementia, but it also

01:32:25.000 provides room for other insults to the brain that are going to be reflected at that level. And it's

01:32:32.920 only when they're reflected at the level that then they, because of this energetic demand,

01:32:37.160 this vulnerability that you alluded to, that then this is going to lead to a cognitive. Why a cognitive

01:32:43.080 problem and not something else? Because when we are engaged in these functions that I explained,

01:32:51.880 we, these functions are not limited to one region of the brain. They are relied on interaction between

01:32:59.080 different regions. So when you're reading something, that information goes to your visual system. But then

01:33:05.320 if you're going to engage learning having to do with that, that will engage other systems. So

01:33:10.840 the memory functions are more distributed. So when you have a more distributed metabolic insult,

01:33:17.400 they're going to be affected. It's just like people know somebody may get a blow to the head

01:33:23.080 and then all of a sudden they may have retrograde amnesia. They may not remember what happened. They may

01:33:29.080 not even remember who they are. And you may not see any significant level of structural or functional damage,

01:33:36.120 but you affected the way the systems were interacted in a more global way. So this is one of the reasons

01:33:43.080 we detect this primarily as a memory problem initially. But later on, it becomes a neurodegenerative disorder

01:33:50.280 when cells cannot longer work without this mitochondrial machinery.

01:33:55.080 Do we have any insight into how much mitophagy or autophagy is going on in the later stages of

01:34:03.160 Alzheimer's disease? In other words, is it possible that so much of this damage is now due to defective

01:34:09.800 cleaning up of the mitochondria? Because the more these mitochondria are damaged, the more mitochondrial

01:34:16.120 DNA is getting released. The mitochondrial DNA itself is actually looks bacterial. So it elicits an immune

01:34:22.200 response. This probably accelerates the process. It would seem that anything that would increase

01:34:28.200 mitophagy or autophagy would at least be able to curb the progression of the feed forward loop on this

01:34:36.200 damage going and accelerating. Wouldn't that make sense? Yes. I agree. However, it's too late. If you

01:34:43.880 already compromise the machinity for obtaining the energy, it's too late at that point. So my focus on the

01:34:51.480 focus of Jack De La Torre and other people is how can we intervene? For example, one way is in the

01:34:59.160 risk factors that have to do with the cardiovascular compromise. Try to intervene with the risk factors.

01:35:04.680 Besides blood pressure, what do you view as the most important risk factors then?

01:35:10.120 I think atherosclerosis is a really important risk factor. And the major blood vessels you indicated,

01:35:17.960 like the carotid, the ascending aorta, and the renal arteries, they are the large blood vessels are

01:35:25.880 the main targets of these atherosclerotic processes, especially at the bifurcation points.

01:35:32.280 The other factors that I would consider would be generalized trauma to the brain.

01:35:38.760 Yeah. I was going to ask you about this. This seems to bear an uncanny resemblance to

01:35:45.240 chronic traumatic encephalopathy, where the difference is if you're a football player or a

01:35:50.440 boxer, you have repeated short bouts of hypoxia. It appears from my reading of the literature that

01:35:57.400 every time you're getting hit in the head, you're having a transient interruption of blood flow. And

01:36:04.280 also it appears based on at least the animal models, we're seeing transient insulin resistance

01:36:10.040 at the level of pyruvate dehydrogenase. So a blow to the head will transiently make it harder for

01:36:16.920 pyruvate to turn into acetyl-CoA, which is the opening substrate in the Krebs cycle.

01:36:23.640 The Krebs cycle. And so while the patients we're describing, who presumably let's just make

01:36:29.080 math simple and say they never get a concussion or a hit in the head, they have this chronic insidious

01:36:35.080 disease process. The athletes who are suffering this type of injury are getting punctuated by spike

01:36:40.840 functions of these, and it doesn't have to be a concussion every time. It could be each play on the

01:36:45.400 field or something like that. Right.

01:36:46.520 Do you think there's an overlap in these processes?

01:36:48.360 Oh yes, completely. This is what's called dementia pugilistica originally. And often

01:36:56.360 nowadays this is confused with Alzheimer's disease and Parkinson's disease. In the case of Parkinson's,

01:37:02.520 is because with the blows to the head, there is a rapid twisting of the head. When you get a blow to

01:37:09.320 the head, a rapid twisting, bending of the head with respect to the neck.

01:37:14.040 Yeah, it's an angular momentum that usually causes that injury.

01:37:17.880 And this affects the midbrain and the upper brain stem. And actually that's what leads to the knockout.

01:37:24.440 That would feed more into a Parkinsonian phenotype in the midbrain and the substantia nigra.

01:37:30.760 Isolating that region is more vulnerable for this. But it is the same phenomenon. All of these forms of

01:37:36.600 dementia will have a common denominator at some point, regardless of the many different ways that you

01:37:43.160 can impact the system. The most likely common denominator would be at the level of the mitochondrial

01:37:48.760 respiration. And therefore, another way, for example, the circulation may not be a good target

01:37:55.320 for neurotrauma. But if you find a way to facilitate mitochondrial respiration, even if there is compromise,

01:38:05.880 hyperperfusion or some other condition. And this is what I've been working on for many years.

01:38:12.360 And once we discovered that the main problem in the Alzheimer's brain had to do with this

01:38:19.800 inhibition of cytochrome oxidase, we set out to how can we intervene? Is there any way?

01:38:26.040 And you have two interventions that you have now coupled that both work on cytochrome C,

01:38:32.120 but in a slightly different way.

01:38:34.200 Yes. Cytochrome C oxidase. Cytochrome C is the carrier and cytochrome C oxidase is the large

01:38:39.960 enzyme. The large complex. Yeah. Thank you for clarifying.

01:38:42.200 So the first one, I use a pharmacological approach because I was more familiar with those approaches,

01:38:48.040 but I couldn't do it with regular. Most of what is called neuropharmacology or psychopharmacology

01:38:54.680 is really aimed at neurotransmission, resectors and agonies and antagonists. What's needed here is

01:39:02.340 something is acting at the level of mitochondrial respiration. And reviewing all literature from the

01:39:08.260 1960s, I found out that methylene blue, commonly used compounds in the lab, was able to act as an

01:39:17.940 electron donor. And depending on the conditions, but if you make it in a very low concentration,

01:39:24.340 it acts as an electron cycler. It will donate, but it will also get electrons from other compounds,

01:39:30.020 and it will continue to feed into the electron transport as an alternate route. And in fact,

01:39:37.780 if you block, for example, complex one with rotenone that you're interested, still the electron

01:39:44.740 transport can proceed going through methylene blue as a bypass. Because in a normal organism,

01:39:51.780 complete blocking of complex one would be fatal. You're saying with a high enough concentration of

01:39:56.340 methylene blue, you can still get electrons past the bottleneck of complex one.

01:40:02.420 We can prevent in animal models degeneration. We've shown this in many preparations. We first

01:40:09.140 did it in the retina because it was more accessible and we could manipulate that locally as a model of

01:40:14.660 the brain. And then we did it in the brain. So this has an interesting history, right? There's a guy

01:40:19.380 named Paul Ehrlich who studied this, right? And the only reason I remember this is-

01:40:23.460 Yes. One of my heroes.

01:40:25.460 Really? Yeah. Well, I read something that I love where expressions come from. And so there's an

01:40:31.380 expression, balls to the wall, which means like going very, very fast all out. And most people

01:40:36.820 don't realize, but it just refers to a governor and a train where the governor, the faster that the

01:40:41.700 train was going, these balls that were hanging on, basically cables would move further and further out

01:40:47.300 as the centrifugal force goes. And once they touch the wall, that's the mechanism that would regulate

01:40:51.700 the speed and slow it down. But there's another expression that comes from Ehrlich's work, which is,

01:40:56.340 is it a magic bullet?

01:40:57.460 Magic bullet. And he referred to methylene blue as a magic bullet. And Ehrlich, Paul Ehrlich,

01:41:03.700 he worked in Berlin, Berlin, Germany. And he was able to be part of a very progressive group at the time.

01:41:12.260 And- This was before World War II. This was in the-

01:41:15.060 Yeah. This is-

01:41:16.180 Actually, this is in the late 1800s, right?

01:41:17.700 No, no. This is in the late 1800s.

01:41:19.300 Yeah, yeah, yeah.

01:41:19.860 Yeah. 1886, he was working on this and he injected. At that time, it was the beginning

01:41:25.300 of the Industrial Revolution. And the first thing in the Industrial Revolution that was developed

01:41:29.540 were the textiles, being able to manufacture clothing. And one of the important things was the

01:41:35.380 transition from using natural products for dyes to develop chemists developing synthetic dyes.

01:41:43.300 And actually, Germany led this process and methylene blue was one of these synthetic dyes,

01:41:49.060 blue dye. And for many decades, it was the blue dye used in blue jeans and most of the other blue

01:41:56.500 clothing. So one of the things that intrigued Paul Ehrlich was that he injected methylene blue,

01:42:04.580 one of these neosynthetic dyes, into a live rat. And then he dissected the animal. After killing

01:42:13.300 the animal, he dissected the animal. And he found out that the methylene blue, this was a large

01:42:19.460 concentration intravenous injection, was primarily staining nervous tissue, the brain and peripheral

01:42:27.540 nervous tissue. So he created the concept there of a magic bullet. This is a chemical that, remember

01:42:36.260 this in the 1880s, this is a chemical that I'm giving systemically, yet it is somehow finding its way

01:42:44.500 to the nervous system. And it's becoming trapped there, as you can see by the stain. Later, this phenomenon

01:42:51.940 was called supravital or vital staining. And it was exploited, for example, by Santiago Ramón y Cajal,

01:42:59.940 one of my other heroes during this time. He referred to this as the Ehrlich reaction,

01:43:06.420 to be able to stain nervous tissue when the animal was alive. But what does it mean, the animal being

01:43:11.780 alive? The animal respiring, the animal using oxygen. So methylene blue, they didn't know this,

01:43:19.380 but methylene blue has affinity for these redox reactions that are happening in a maximized way

01:43:26.420 inside the mitochondrial in the electron transport chain. And especially at low concentrations,

01:43:32.820 it becomes trapped for periods of hours inside mitochondrial. It can work as a mitochondrial stain.

01:43:39.620 Does it become toxic? What does the toxicity look like at a higher dose?

01:43:43.460 At a higher dose, instead of acting as an electron cycler, it actually replaces oxygen in the,

01:43:51.140 you know, it competes with oxygen. Remember that I told you oxygen was the one that was taking the

01:43:56.020 electrons. So he can be, you wanted to have it in a low concentration that is giving electrons and

01:44:04.260 taking electrons at the same rate. But you're saying at a higher dose, it becomes a proton acceptor.

01:44:09.300 A little, yes, because it competes with oxygen and it oxidizes the tissues. And actually,

01:44:16.900 that was in part the first application that Ehrlich found for methylene blue.

01:44:23.140 So that's interesting because the only time obviously that

01:44:26.500 I've ever seen it used is for treating methemoglobinemia in the emergency room. So

01:44:30.980 someone is exposed to carbon monoxide, you know, acutely or even chronically over a long

01:44:35.860 enough period of time, this basically breaks it apart. So there you actually want it to

01:44:41.700 sort of out-compete oxygen a little bit, right? Is that what's happening there?

01:44:45.460 Yes, yes. No, what is happening there in the carbon monoxide occupies the, in the heme molecule,

01:44:51.540 the pocket where normally oxygen finds. That's right. So you actually wanted to-

01:44:55.460 A competitor. Yeah. You wanted to get the carbon monoxide out.

01:44:59.220 That will displace it. And methylene blue will do that. But because you do this infusion,

01:45:05.860 so methylene blue can be used to prevent or rescue you from methemoglobinemia,

01:45:15.300 this inability to bind the oxygen. But a higher concentration induces methemoglobinemia.

01:45:22.740 Yes. The same compound. So this is typical of all of these redox chemicals that I studied. They

01:45:30.100 have this- They have bimodal functional points.

01:45:32.420 Yes. We call this biphasic dose response or hormetic dose responses. Essentially they do the

01:45:39.620 opposite effects, low and high concentrations. Now the color, the other, if someone's listening to

01:45:46.100 this, they'll remember the high school chemistry class. How do you demonstrate this to your students?

01:45:50.420 Yes. Well, when you add the powder of methylene blue into water, the water becomes very blue. And

01:45:57.700 then if you use a reducing agent, and I use vitamin C, ascorbic acid, because it's a

01:46:05.140 effective reducing aging, but it's harmless. When the methylene blue is reduced, it becomes transparent.

01:46:11.300 Reducing meaning it's accepting protons.

01:46:13.620 Yes. It's no longer acting as oxygen.

01:46:17.300 So then you'll turn that vial clear.

01:46:19.860 Clear. And this is, then you refer to it as leucomethylene blue. Leuco actually comes like

01:46:26.180 the same root, like leukocytes, the white blood cells.

01:46:28.900 Yes.

01:46:29.460 So you call it the leucomethylene blue. That refers to the methylene blue being in the reduced

01:46:34.980 state as opposed to the oxidized state that is the blue. So methylene blue had major advantages,

01:46:42.180 but one of the cosmetic disadvantage is that once it goes through this process that I explained that

01:46:49.060 becoming trapped that was discovered by Ehrlich of becoming trapped in the nervous tissue. So it has

01:46:53.700 affinity for nervous tissue inside mitochondria. Eventually it goes back into the circulation. It

01:47:01.300 takes a half-life of about 12 hours with a dose that is a low dose that produces this

01:47:08.260 redox benefit. So it concentrates in the urine in the bladder. And actually here in the U.S. for

01:47:15.060 decades before the antibiotics were available, if you had a urinary bladder infection, you took

01:47:22.820 methylene blue pills. The methylene blue pills will start increasing the concentration of methylene blue

01:47:28.660 inside the bladder until it became a pro-oxidant while it was there. And it eliminated any bacteria

01:47:36.100 or virus in a non-specific manner. And it was a very effective, more effective way to eliminate

01:47:44.340 urinary bladder infection. For example, in older people that have chronic problems that they go through

01:47:50.100 round after round of antibiotics that debilitate them or create resistance, you could use methylene

01:47:57.860 blue. And is it because the methylene blue would, at a dose that was not toxic to the human,

01:48:03.700 once it concentrates in the bladder, it increases its concentration and therefore is toxic to the

01:48:08.260 organism? It will become oxidative and it will be toxic for the bacteria. Oh, so is it a Ross-induced

01:48:14.180 injury to the bacteria then? Correct. Ah, so you're basically going after the mitochondria of the

01:48:18.740 bacteria. Yes. Yes. It does the opposite, but it does it to the microorganisms that are inside the

01:48:24.900 bladder that are producing the infection. So it has the potential to do this in other situations,

01:48:30.900 but here naturally concentrates there. So that provides the advantage. But there are many things

01:48:37.060 about methylene blue I would not go into, but Ehrlich himself determined that the parasite that produces

01:48:44.500 malaria. The Plasmodium falciparum had an enzyme that was particularly vulnerable to not much large

01:48:54.500 concentrations of methylene blue were enough to affect this enzyme. So methylene blue became the first and

01:49:01.700 for a long time the only treatment for malaria. And this was a major breakthrough in medical research,

01:49:09.540 was in fact the first synthetic chemical used for a medicinal application in the history of medicine

01:49:17.540 and pharmacology, was methylene blue. And all of the first synthetic medicines were derivatives of

01:49:26.420 methylene blue, including in particular the late 1940s, early 1950s, the development of chlorpromazine,

01:49:34.420 chlorpromazine. The first psychopharmacological agent that was used for psychosis or what we call now

01:49:40.420 schizophrenia, in those days they would call it dementia precoce, because they were thinking that

01:49:47.140 it was the same kind of dementia that was happening in the older people, happening in the young people.

01:49:51.780 Now we make a separation between dementia and schizophrenia, but chlorpromazine is a methylene blue

01:49:57.700 derivative, and in fact there are reports as far as 1930s of physicians giving methylene blue mixes.

01:50:05.220 The problem was that in the original way that methylene blue was synthesized for textiles, there were a lot

01:50:11.860 of intermediary products as a result of the synthesis, and some of these were likely chlorpromazine.

01:50:19.780 So they were seeing anti-psychotic effects from giving these methylene blue preparations,

01:50:24.980 as I found reports in the 1930s and 1940s, and then it was picked up by a pharmaceutical company,

01:50:31.860 and by the end of the 1940s they developed chlorpromazine as the first anti-psychotic

01:50:37.540 medication, and that would change completely the face of psychiatry.

01:50:41.300 And it may have just been simply a chemical contaminant slash intermediary contaminant within

01:50:46.100 the formulation of methylene blue. So they thought the benefit was methylene blue,

01:50:50.980 it was actually from a byproduct within.

01:50:53.300 And they discovered what the byproduct was.

01:50:55.940 Which is such a great story of chemistry in general, right? How easy it is to be fooled by

01:51:02.500 something that seemingly makes sense. Now today, the only FDA indication to my knowledge for

01:51:07.860 methylene blue is methemoglobinemia. Is that correct?

01:51:11.140 Yes.

01:51:11.460 I mean, there's clinical trials that are going on to study this in Alzheimer's disease.

01:51:15.300 Yeah, let me clarify that because what happened is that methylene blue was being available for 120

01:51:22.100 years plus. So, methylene blue was grandfathered by the FDA. It preceded the creation of the FDA. So,

01:51:31.620 the FDA has not been able to resolve well how they deal with these grandfather drugs. Being the first

01:51:40.500 synthetic drug available. So, it was used for many things. I'm not going to go into all of them,

01:51:46.100 but malaria was probably the most important one until some Spanish and French explorers in South

01:51:53.460 America discovered from the bark of the tree, quinine. And then that happened and it became the next

01:52:00.420 generation after methylene blue. Nowadays, they're bringing back the methylene blue, especially in Africa

01:52:06.340 because there the plasmodium has become resistant to quinines. So, they are combining it. So, there's a

01:52:13.780 comeback for methylene blue in that respect. So, it is used medicinally for that. But the FDA never really

01:52:23.060 got to have a saying on it. So, what you're referring to is what has survived in what is called the U.S.

01:52:32.100 pharmacopoeia, these compendions of medications with indications. And in the U.S. pharmacopoeia,

01:52:39.460 that indication of methylene blue for methemoglobinemia has survived. Some of the others have been removed,

01:52:46.020 like I told you, for urinary bladder infections when the antibiotics became available. But it's being used

01:52:52.020 to protect the brain. You mentioned cancer early before we started the interview. Many of the drugs

01:52:59.300 that are used for chemotherapy have side effects that affect the brain, in particular mitochondrial

01:53:05.060 respiration. So, methylene blue, given before or during chemotherapy interventions, have been found to be

01:53:13.380 life-saving. One example is one called ifosfamide. So, ifosfamide-induced encephalopathy

01:53:21.620 happens in this chemotherapy. And there are many papers on this. However, the problem is the FDA will

01:53:30.900 not acknowledge these uses because there is no pharmaceutical company who is bringing these

01:53:37.140 materials. I guess this is sort of an impossible situation to understand because the FDA can't really

01:53:43.300 consider the approval for an agent or a use without an investigational new drug filing, an IND. There is

01:53:51.140 no IND, I assume, for methylene blue because there's no economics in methylene blue.

01:53:56.260 Yeah. There is no company that wants to invest because it's not patentable. They cannot protect

01:54:02.980 there with a patent. So, anybody can manufacture methylene blue and prescribe it or use it. In some

01:54:09.700 countries like Canada, it's freely available. Here in the US, it's unclear what its status is, but you can

01:54:18.020 get it through the internet. The problem is there are two problems. One, you have different purities. So,

01:54:26.020 you have at least three categories of purities for methylene blue. The one that should be used by in humans,

01:54:32.580 like in the emergency room, is the so-called pharmaceutical quality or the US, we call USP

01:54:41.460 grade. The Europeans have a similar, but the one in the USP is actually more restringent than the

01:54:48.340 European methylene blue. Then there is chemical quality that is used in laboratory for staining,

01:54:55.060 but that can go, for example, the one produced by Sigma has about 15% impurities. It should not

01:55:02.180 be given to live animals or humans and is readily available. So, I always want to warn against that.

01:55:10.020 And in many experiments with animals, they use that Sigma product. So, we don't know if we're confounding

01:55:15.780 the results of the experiments with the impurities. And impurities are very toxic. It has lead, it has

01:55:21.140 mercury, it has cadmium, it has a number of neurotoxic impurities. And then the other one is even less

01:55:27.700 pure is the industrial color of the genes to color the blue genes and other things. And that is even

01:55:33.380 more than 15% impurity and nobody knows for sure. Now, there was a company in Scotland several years

01:55:40.900 ago that ran a compound, LMTM. And the trial, which was announced, results of this trial were announced

01:55:49.140 about two years ago. And it was a big hoopla because the study, which I went back and skimmed the other day,

01:55:55.060 because I knew we would probably, I was hoping we would talk about this. The study basically

01:55:59.300 took patients in early stages of dementia, randomized them to various interventions,

01:56:03.460 but one of them was this agent, this LMTM, which they described as a methylene blue derivative. I don't

01:56:09.380 know how far a derivative it was. It might've been not much of a derivative.

01:56:13.860 It's essentially, you remember when I told you I added ascorbic acid and reduced methylene blue. So,

01:56:19.940 they've done something like this. They have reduced methylene blue, but they don't

01:56:24.340 use the name methylene blue. They use the name of methyltheonine chloride, which is a more chemical

01:56:31.300 name. And that's where the MT comes. And then the L is for the leuco.

01:56:36.260 Because it's clear. It comes in its reduced form.

01:56:38.740 Yeah. That's the form that is in the pill.

01:56:41.300 As soon as it's in the body, it's oxidized.

01:56:43.220 Yeah. It starts these redox cycles.

01:56:45.380 And those patients did void blue.

01:56:48.180 Oh, yes. So it is clear that it's doing the redox cycles.

01:56:51.940 Now, what was very controversial about this was the primary endpoint of that study

01:56:58.660 was a neuroimaging outcome, and the primary output failed. There was no difference on neuroimaging.

01:57:09.620 There was a secondary outcome on cognitive function. And in a subgroup analysis, which again,

01:57:16.420 the statisticians will say, they cry foul, right? And understandable. You can't start parsing the data.

01:57:21.540 And I agree.

01:57:22.420 Yes. But the argument was the subset in which this benefit was seen, which was about 15%. And if I

01:57:29.700 recall, it was only patients that received the LMTM in monotherapy. So what we don't know,

01:57:34.820 unfortunately, because this to me left a lot of questions unanswered, right?

01:57:38.980 It certainly suggested there's something going on with methylene blue.

01:57:43.060 But are we being misled because the combination of methylene blue

01:57:47.300 with other drugs obfuscates the results?

01:57:50.260 Yes. I think that's the most likely.

01:57:52.900 That's one? Yeah.

01:57:53.380 No, it is the most likely.

01:57:54.340 You think that's the most likely explanation?

01:57:55.460 Oh, yes. However, let me clarify. These individuals have never presented methylene blue

01:58:01.460 or understood methylene blue from the point of view that are being presented to you as a metabolic

01:58:07.060 enhancer, or it could be a metabolic poison too, but in low concentrations.

01:58:12.260 At the right dose, yeah.

01:58:13.380 The low concentrations as a metabolic enhancer acting on the mitochondrial respiration.

01:58:19.060 They have been presenting these as an anti-tau medication.

01:58:23.860 That's correct. The entire company, which whose name I forget now.

01:58:27.620 Yes. It's called Tau X.

01:58:28.900 It had Tau in the name.

01:58:30.100 Tau X.

01:58:31.060 Yeah. Yeah. That's the other thing that interested me, which was...

01:58:33.700 The hypothesis is completely wrong.

01:58:36.100 They might have backed into something interesting potentially.

01:58:38.660 Yes. And I say this here publicly. It is unfortunate that they have done this this way

01:58:46.180 because they are undermining the potential benefits of methylene blue. The biochemist who is behind

01:58:54.500 the hypothesis I'm not going to name, he found that in vitro at relatively large concentrations to

01:59:03.940 based on what I'm telling you about mitochondrial respiration, it prevented the phosphorylation

01:59:10.580 and agglutination of Tau in vitro. So they then infer, oh, this is an anti-Tau agent.

01:59:20.100 If you test methylene blue with immediate different compounds, depending on the concentration of

01:59:26.900 methylene blue, because it has reducing or an oxidating action, it will interfere with all kinds

01:59:33.300 of phenomena. There's nothing specific about methylene blue.

01:59:36.180 This may be true, true, and unrelated. Its effect on Tau, whether correct or incorrect,

01:59:42.340 may not actually matter.

01:59:43.620 And not only that, the effect is dose dependent. In other words, in vitro,

01:59:49.380 the more concentration of methylene blue had, the more you interfere with the Tau aggregation.

01:59:54.660 In other words, you don't see this bimodal dose response.

01:59:57.460 No, because they were actually working on the high end of concentration.

02:00:02.260 So does that mean they weren't even looking to see what the toxicity was in the mitochondria when

02:00:06.660 they did the initial work?

02:00:08.100 They did some later work to address this when they wanted to move this to the FDA. But the point is,

02:00:16.580 in the first studies from this group, the most effective dose was the lowest dose.

02:00:22.340 And it was in the monotherapy group?

02:00:24.260 Yes. No, no. This was before that study.

02:00:26.340 Oh, okay.

02:00:26.740 Before that study that you're citing.

02:00:28.980 Oh, this is the phase two.

02:00:30.340 This might have been the phase one.

02:00:32.980 In the first study, they found some effect with the very low dose. And in the higher doses that

02:00:40.740 would approximate these anti-Tau effects, they found no effects. And they turned this around

02:00:47.540 in such a way that in one of the papers published in the Journal of Alzheimer's Disease, that a friend

02:00:54.420 of mine is the editor, they claimed that actually the highest dose, there was a problem with

02:01:01.460 absorption. And it was really a low dose. And the lowest dose was more easily absorbed. And it was

02:01:11.860 really then the high dose. And then they changed the results to indicate, oh, the low dose was the

02:01:19.700 high and the high dose was the low. And that's why it worked. So in other words, they did not change

02:01:24.740 their hypothesis that was contradicted by their data, which is the same thing that's been happening with

02:01:30.820 the amyloid people. Their results do not support the hypothesis and they keep blindly moving forward. 1.00

02:01:37.140 So now what you explained was because they have difficulties getting a patent for this compound,

02:01:45.540 they created this reduced version of methylene blue and did similar studies. But in that study,

02:01:54.020 they had the problem that the majority of the people, if you are having Alzheimer's disease and you're

02:02:01.460 in a hospital or being treated by usually neurologists or sometimes psychiatrists, they would prescribe,

02:02:08.740 unfortunately, unfortunately, drugs that have no benefit to the patients, but produce adverse effects

02:02:17.140 such as cholinesterase inhibitors and memantine. And the idea being is, well, this is the standard

02:02:23.780 of care. It would be, quote unquote, unethical to take these patients off these agents, even to allow

02:02:29.140 them to enter another trial. Well, that may be the reasoning that some people may have, but that's

02:02:34.500 actually the opposite of what's happening. These drugs are ineffective and it's unethical to continue

02:02:40.900 to use these ineffective dose that are having these toxic and adverse effects on people. If you go back

02:02:48.100 to the original studies that were used by the FDA to approve these drugs and the reviews that were done

02:02:54.900 subsequently by like the cross-chain groups meta-analysis, they all conclude very clearly that these drugs

02:03:02.260 are ineffective and they do not improve activities of daily living and that the disease continues and

02:03:10.340 progress and people die. In fact, in countries where they have more elaborate longitudinal data like in

02:03:17.460 the UK of administration of these compounds to patients with Alzheimer's, they know

02:03:24.900 that they die sooner if they're taking these medications that the ones that refuse to take them.

02:03:31.380 And the UK made an attempt. In fact, they banned these compounds because they had evidence-based

02:03:37.860 that not only they were ineffective, but they were counterproductive. And within a year,

02:03:43.380 the public demanded to the politicians because if they're used in the US, they must be beneficial.

02:03:52.020 And so this is a decision that was done politically motivated to bring them back and make them

02:03:58.900 available, even though we have all the evidence, just like we have against the amyloid hypothesis,

02:04:05.620 that the cholinergic hypothesis of Alzheimer's disease is also irrelevant.

02:04:10.820 Actually, it's funny. I didn't realize people still subscribe to that hypothesis.

02:04:14.660 The most commonly prescribed medications are the cholinesterase inhibitors. And then the FDA did

02:04:21.540 not approve memantine for early Alzheimer's or mild Alzheimer's or mild cognitive impairment. They

02:04:29.140 approved originally only for severe and then later for moderate and severe, which was very unfortunate.

02:04:36.740 The memantine is preventing some of the excitotoxicity that is damaging those hippocampal cells.

02:04:43.300 But essentially what you're doing when you do that, you are rescuing from dying a cell that is

02:04:50.340 functionally incompetent. 0.79

02:04:52.180 Yeah. So indirectly, which is interesting because there was a study that came out about a month

02:04:56.420 and a half ago on memantine. And I remember, you know, this is obviously not my field of expertise.

02:05:00.260 So my level of knowledge in the literature is so much less than other areas. But the problem with

02:05:05.940 that could be that you're actually rescuing a cell that's going to go on to send a signal that could

02:05:12.340 cause more damage down the line.

02:05:13.860 It is completely counterproductive. And it's based on the pathology, pathology oriented,

02:05:19.540 that you can see more of these neurons there when the people die.

02:05:22.980 But it's not a functional assay. In other words, it's a neuropathological, which there's,

02:05:28.100 there's value in these things, but it sounds like the real overarching challenge here is

02:05:32.500 triangulating between neurobiology, anatomy, functional signaling. And then of course,

02:05:37.700 ultimately clinical outcomes matter more than any of these other things in the end.

02:05:41.700 I agree. And that's what should direct all of this in the first place. And it's not what's happening.

02:05:47.700 Now, I know this is a little outside of the work you do, but do you have a point of view on the

02:05:52.260 recent excitement around herpes simplex virus one? Have you followed that discussion?

02:05:57.620 No, no. I don't have a good point of view. What I can tell you is we found another way

02:06:03.460 to try to intervene with mitochondrial respiration using light, in particular infrared light that can

02:06:11.140 go through the tissues. And the photons in the near infrared light are absorbed by cytochrome oxidase.

02:06:20.180 It turns out that cytochrome oxidase, that's the name cytocell, but chrome color,

02:06:26.260 is because of it absorbs certain wavelengths and it reflects others. So it's the chemical in the cell

02:06:32.420 that gives color to the cell. And this property of photonic absorption we have used in conjunction

02:06:40.500 with the laser delivery of near infrared light transcranially through the forehead as a source of photons

02:06:48.580 that actually oxidizes, photo oxidizes cytochrome oxidase. And by doing that, the enzyme has more

02:06:56.820 affinity. That's the conformation of the enzyme that has more affinity to oxygen, peroxygen consumption.

02:07:04.020 Yeah, I just pulled out a picture that we'll make sure we link to in the show notes that comes from

02:07:08.740 one of your papers, actually, where it shows in the same figure a close section of the mitochondria.

02:07:14.020 And you can see the effect of methylene blue and also the effect of near infrared light. Now,

02:07:20.260 it strikes me as interesting that you can get the wavelength just right because you have to

02:07:24.180 be able to get through not just the tissue, but the skull itself.

02:07:27.140 Actually, the skull is less of a problem. It's easier to go through.

02:07:30.580 Because it's porous because of the bony matrix?

02:07:32.500 Yeah, because there is less circulation through it. One of the big bromophores that we have is hemoglobin.

02:07:39.540 I see. So hemoglobin can absorb and reflect much of this light before it actually reaches the neurons.

02:07:44.340 So what we try to do is we move away from this peak of exhaustion, so oxy and deoxy hemoglobin,

02:07:51.620 to one that is still can be absorbed by cytochrome oxidase.

02:07:56.020 So how many nanometers then?

02:07:57.620 We use 1,064 nanometers wavelength, so around 1,000, which is a wavelength that is not very well studied

02:08:06.500 in biochemistry. Most of the spectrophotometers in biochemistry, they do not go all the way to 1,000.

02:08:13.700 Yeah, they're in the hundreds, usually.

02:08:15.300 Yes, they usually end up.

02:08:16.740 300 to 800 or something.

02:08:18.020 Yes. But the longer the wavelength, the more it penetrates to the tissues.

02:08:24.500 How do we know how safe that is? I'm sure somebody listening to this is going to say,

02:08:28.820 wait, that sounds like microwaving my brain.

02:08:32.500 Of course, it's a different wavelength. No, I understand. But as the sort of lay person,

02:08:36.180 this sounds very scary, right?

02:08:37.620 Yeah, microwaves moving the other direction. But the longer the wavelength, the less energy they

02:08:42.580 carry. So the less they can penetrate. So they cannot really penetrate inside atoms,

02:08:48.260 like the ones that have short wavelengths. But they are good enough to penetrate to the tissues,

02:08:54.740 not very deep. And only about one to two percent, if we do it transcranially through the head,

02:09:01.220 actually goes through to the surface of the cerebral cortex. Once in the cerebral cortex,

02:09:07.380 the white matter is also a barrier. So the effect of the photons is primarily in the gray matter layer of the cerebral cortex.

02:09:17.780 And what it does is you're donating these photons to the electron transport. So you're bypassing

02:09:25.380 the electron donors. The photons are not identical to electrons, but they act in a similar way in the

02:09:33.700 electron transport. So the photons and the electrons are very similar. The difference is that the

02:09:39.460 electron can carry a very small mass. The photons essentially do not have mass. And by providing

02:09:46.260 photons to the electron transport, you keep the electron transport going, because these enzymes

02:09:51.460 engage in the redox changes. And the more photons you send to cytochromoxidase, the more of the

02:09:59.460 enzymes quickly goes to the oxidized conformation. And that oxidized conformation is the one that has

02:10:05.780 more affinity to bind oxygen. But I don't understand, how is this actually making its way systemically to

02:10:11.780 the brain through a transcranial stimulation? When you aim through, for example, the forehead,

02:10:18.900 it goes through the tissue and reaches the surface of the cerebral cortex. And that's how it makes its

02:10:26.980 way. It's more localized. It's different from, it's not a systemic administration like methylene blue.

02:10:32.980 And is it enough to just be able to hit the frontal cortex to create a clinical improvement without

02:10:40.100 impacting the mitochondrial function deeper in the midbrain or lower part of the cortex?

02:10:46.340 To create a functional improvement. We don't know yet about clinical. Especially,

02:10:52.020 I would not say that in somebody with the degree of atrophy that many of the Alzheimer's patients

02:11:00.100 have, we're going to have enough substrate there to be able to stimulate and reverse the disease. So

02:11:08.660 this will have to be tested with clinical population. Are there clinical trials that are

02:11:13.460 going to be looking at this near-infrared light strategy combined with methylene blue?

02:11:18.660 No, not combined. You don't think of these as synergistic. You'd consider these separate

02:11:23.140 approaches? Yeah. I consider them separate approaches. The reason for this is the following.

02:11:29.300 Methylene blue can affect these photons. Ah, of course. That makes sense. Yeah.

02:11:34.900 And this is actually used nowadays. For example, dermatologists, if you have a melanoma,

02:11:43.300 a cancer in your skin or any other lesion, they can inject methylene blue into that region. And then

02:11:50.660 they just shine light and the light- Concentrates the light.

02:11:55.380 Into methylene blue and the methylene blue oxidizes. It has-

02:11:59.780 You had that Ross reaction, the same thing that you see in the bladder.

02:12:02.580 Correct. And it kills those cells there. And this is called photodynamic therapy.

02:12:07.380 It has many applications because if you have a virus that you have no other way to kill,

02:12:13.940 you can always kill it this way. So this is happening. Even people don't know methylene blue

02:12:20.340 is injected into blood that is used for transfusion so that you can then treat this blood with these

02:12:26.740 bright lights. And by photodynamic therapy, kill viruses like the HIV virus or the herpes.

02:12:34.180 Is there a difference between giving the methylene blue orally versus intravenously for this purpose

02:12:39.940 specifically? Yes. The intravenous one, the first target will be the blood cells. So you have to be

02:12:46.820 more careful with the concentration because you don't want to promote the methemoglobinia. In other

02:12:52.660 words, to compete with oxygen. Yeah. So it seems safer to administer orally. Yes. The oral administration

02:12:57.700 produces slower release and in low concentration is very safe. And it's, like I say, it's being done

02:13:06.740 in thousands and thousands of people for malaria. And these studies that have been published in the

02:13:12.980 last few years have primarily given to children in Africa for killing the parasites. And in that case,

02:13:20.500 the oral administration had the advantage that many of these parasites are- In the gut as well.

02:13:24.980 Yeah. In the gut so you can have the higher amounts there.

02:13:28.740 So going back to this broader perspective, I mean, the clear theme here is, which I think is

02:13:34.420 that prevention matters. In fact, we shouldn't be focusing so many resources on the treatment of

02:13:40.260 clinically evident apparent dementia for the reasons you've discussed. So now what we want to do is

02:13:46.020 prevent. I was going to say prevent in high risk individuals, but as one of my friends who's a

02:13:50.340 neurologist would say, anybody with a brain is at risk. So let's stop stratifying as who's high

02:13:55.380 risk versus low risk. Everybody should take a preventative measure. Yes, definitely. In addition

02:13:59.940 to this idea of all the things that matter in the heart. So lower smoking, lower blood pressure,

02:14:05.940 better glycemic control, better management of lipoproteins, et cetera, et cetera. Is there anything

02:14:10.260 that you see as unique in the brain specifically that is maybe not unique or maybe not as important

02:14:16.580 in the prevention of cardiovascular disease? The only one that I would say will have to do

02:14:22.740 with the ketogenic diet. Ketogenic diet will facilitate mitochondrial respiration in a different

02:14:29.620 way, but this will contribute to targeting mitochondrial respiration. So that the brain will benefit

02:14:39.540 more than the heart. The heart will benefit, of course. All of these tissues will benefit, but

02:14:45.220 because of the brain reliance on aerobic metabolism. For example, you alluded, for example,

02:14:51.380 on insulin resistance. One of the problems that happens as the brain ages, even in normal people,

02:14:58.740 is that the transport of glucose is affected. So even though we can increase glucose levels in the blood

02:15:06.100 or what we're eating, we cannot get that glucose being transported to the brain as effectively as in the

02:15:13.140 younger individuals. That's why some of these studies with intranasal insulin administration

02:15:18.340 show transient improvement in symptoms, presumably because they're becoming resistant to glucose. Now,

02:15:24.980 that's obviously not a long-term solution. No. But it illustrates a point. And fortunately,

02:15:31.140 insulin primarily facilitates glucose transports in other tissues other than the brain. The brain

02:15:37.860 actually doesn't require insulin. It can boost its transport of glucose, but the reason for that is

02:15:44.180 that when you wake up in the morning that you have been fasting overnight, whatever levels of glucose

02:15:51.780 are circulating in your blood, then the brain tissue will be the only one that will be able to take

02:15:57.380 that up. And it's only when you have large glucose levels that then insulin is released by the

02:16:03.700 pancreas and then all the tissues then can use it, can feast on it. So the ketogenic diet, so ketone

02:16:11.940 bodies can act as an alternative source for energy in the brain. And the important point is

02:16:19.540 that even though glucose is a preferred substrate during aging, this is compromised, this uptake.

02:16:29.060 However, the uptake of ketone bodies is not compromised. Therefore, you could satisfy some of these

02:16:36.660 nutritional requirements by adding the ketone bodies to the diet. Do you think it matters if a

02:16:44.340 person is on a ketogenic diet or if they're on a non-ketogenic diet, but they supplement with exogenous

02:16:49.860 ketones? I hope it doesn't matter. As long as you have the ketone bodies available, you don't require to have the

02:16:59.220 ketogenic diet itself. But this eventually will have to be resolved empirically. And there is no question that

02:17:07.220 this is going to promote mitochondrial respiration. And we know, as you know, when we're born as infants,

02:17:13.220 we rely primarily for neural function and everything else on these ketone bodies produced by the liver,

02:17:20.980 but because of the kind of lipids that we get through the mother's milk. So essentially,

02:17:27.860 what we're trying to do is bring in somebody who is in all age to rely more on ketosis. That is a process

02:17:36.740 that we know exists under physiological conditions every day. If we go beyond, you know, 12, 14 hours

02:17:43.380 without eating, we start generating this. But it's something that we know in infancy is the primary

02:17:50.260 source for the brain. I didn't realize that. Is that more a result of their livers not being able to

02:17:55.780 release enough glycogen via glucose and hepatic glucose output? I mean, I know they have a very

02:18:01.060 high demand for energy. Yes. Can you measure the ketone in their blood? Yes. But it is because of

02:18:06.980 the source of food that they're taking. I see. So they're basically getting

02:18:10.420 medium chain triglycerides through the milk. Exactly. Yes. The medium chain triglycerides

02:18:14.820 being the main source there for energy conversion as opposed to some of the other triglycerides.

02:18:20.500 So the original bulletproof coffee is actually mother's breast milk before it is...

02:18:25.140 That's right. The fancy coffees that everybody drinks. Yes. So I do believe that that's another

02:18:31.220 alternative. So in essence, you could potentially have pharmacological interventions that address

02:18:38.180 mitochondrial respiration, but they will not have to be classic pharmacology like neurotransmitter-based

02:18:44.020 pharmacology. There will be more of a metabolic pharmacology. You can have near-infrared light by

02:18:50.260 providing this photonic stimulation. However, that one is targeted. It's not systemic like you pointed

02:18:56.980 out. So one will have to find the target. Luckily, the forehead is more accessible. We don't have hairs.

02:19:03.620 And we can target that prefrontal cortex that shows the initial cognitive difficulties as people become

02:19:11.380 older. And that's what we have been doing. And then the third one will be through the diet, which you

02:19:17.060 facilitate. Because as you pointed out, the insulin resistance is because our glucose levels are going

02:19:23.140 up because we cannot transport it into the tissue, especially nervous tissue, which was a primary

02:19:29.140 consumer has effectively. And then we have these high levels of glucose for longer times. So there's more

02:19:35.780 insulin that is being released. And then this desensitizes the receptors. So there is a natural

02:19:43.380 development of metabolic syndrome as we grow all because of this phenomenon. This manifests itself

02:19:51.060 then has less substrate for energy for the brain. And then you have a cognitive decline

02:19:56.980 accelerated associated with obesity and hypertension and this insulin resistance. So it's all part of the

02:20:05.620 same age-related picture. And probably people eat more because they are trying to make up for this lack

02:20:12.660 of energy that the brain is consuming. And if any organ is more liable to influence our eating behavior,

02:20:21.380 it will be the neural tissue. That's such an interesting thought because I've always believed,

02:20:26.340 as you've suggested, that I think our appetite is driven by fundamentally important physiologic

02:20:32.020 processes. And starvation would be the most important among them. And starvation in the modern world

02:20:37.860 doesn't look like starvation in the prehistoric world. Starvation in the modern world can be

02:20:42.420 in the presence of obesity because we're not talking about the obvious, we're talking about

02:20:47.620 the cellular level. And so if cellular metabolism is deficient, which is often the case in insulin

02:20:53.060 resistance, an individual can be functionally starving and that can drive it. Now, I've always

02:20:58.180 thought about it through the lens of the liver, but you're making an argument that says there's also a

02:21:02.020 central starvation that could be also driving these repetitive changes. Yes. But there are also

02:21:08.180 peripheral components, like you say. For example, in the case of the obese, an individual that has

02:21:14.740 obesity will, by almost definition, will have down-regulated the ketogenesis. The ketogenesis

02:21:25.300 enzymes will not be upregulated unless you're consuming your own fat. And these are trainable

02:21:34.020 enzymes, like inducible as well. So if you don't go through periods of fasting, you cannot elevate

02:21:42.900 these enzymes. So somebody who is obese and suddenly stops eating is starved because his body cannot,

02:21:52.180 it doesn't have the metabolic presence of hyperinsulinemia. It is a very painful transition

02:21:58.100 into fasting. You cannot use your body fat to, to feed, especially the brain, which is the first

02:22:04.020 one that is going to give you these signs and symptoms. So the first thing that somebody has to

02:22:09.060 do is start out by having a periodic periods of fasting that in, in my own case, I do it once a week,

02:22:16.660 usually between Friday and Saturday. I fast for at least 14 or 16 hours. You know, it's not difficult

02:22:23.700 to do. If you have an early meal and then a late brunch, you will have significant fasting and you

02:22:29.780 can accelerate that process by consuming some of the circulating glucose if you do a workout that

02:22:36.580 morning. So by doing that, I am allowing my body to build up these ketogenic enzymes. And therefore,

02:22:45.620 then during a regular day in the week, if I don't eat anything between meals, I don't feel hungry

02:22:52.660 because I can consume my own body fat. And people who are obese cannot do that. They don't have the

02:23:01.220 biochemical machinery to do it. So I believe that's probably the third way of approaching this problem.

02:23:07.860 If those three things could be used, and like I say, it may not be possible to combine some of them,

02:23:13.700 like I will have to empirically determine how much methylene blue one can have systemically

02:23:18.900 so that to not produce a photodynamic effect. When I do transcranial laser stimulation,

02:23:26.420 we hope in the future we may be able to do this with LEDs. Right now with the LEDs are

02:23:32.740 commercially available. We haven't been able to find the results that we get, but we, we are investing

02:23:39.460 time in trying to, to change this so it will be safer and cheaper to do. So right now the only ones,

02:23:48.420 so my bioengineering colleagues has been able to collaborate with me and develop a device that we

02:23:56.260 can transcranially do imaging with near infrared spectroscopy and actually measure the concentrations of

02:24:04.820 those oxidized cytochrome oxidase in vivo in the human brain. And we published that last year.

02:24:10.980 And this allows us to directly have a measurement that we are indeed engaging our target. And this

02:24:18.980 also will allow us to find what is the optimal dose response for that particular brain. Because like you

02:24:25.940 indicated, different people have different heads and the transmission would not be equivalent.

02:24:31.060 So this is what we're doing. And so we have obtained three major grants for doing this with the

02:24:37.780 bioengineering group in the Dallas area. For example, Professor Hanley Liu, we are doing the

02:24:44.580 development of these devices to monitor the physiological changes. And this is a grant by NIH that is called the

02:24:52.980 Brain Initiative Program. And then here with my colleague Andreana Halley, we are, have a grant from the

02:25:01.140 National Institute of Aging to test this transcranial near infrared light in older people and people with mild

02:25:09.780 cognitive impairment. And then the third has been a benefactor who's giving us large amounts of money so that we can

02:25:19.780 pursue this line of work with the transcranial lasers. And I can show you the endorsement from

02:25:27.140 some of the people in the field. Oh yeah, I'll take a picture of this and we'll put this on. In fact,

02:25:32.180 it was actually Jack who directed me to speak with you maybe six months ago. This is exciting. You know,

02:25:37.860 I want to add one other thought to this, which is I hope that if somebody's listening to this who's involved

02:25:42.500 in traumatic brain injury, that someone ought to look into a clinical trial of using methylene blue

02:25:48.740 as a rescue agent during periods of traumatic injury, because again, mechanistically, it's at least

02:25:54.260 plausible that you could salvage and rescue some of the transient insult and the damage that goes through

02:26:02.340 that. And again, there's another example of a disease for which we don't seem to have any solution

02:26:07.860 other than the obvious, which is avoidance of the injury, the insult. But there's still

02:26:12.660 a lot of people out there that are being exposed to repetitive head trauma. And as you probably know,

02:26:18.980 there's been some interesting hypotheses around the presence of ketones in the system before

02:26:25.220 traumatic injury and potentially a salvage after. But it seems to me that this methylene blue story

02:26:30.260 probably deserves a bit more attention in other areas, given these properties you've described.

02:26:34.900 I actually agree with you. And I would say, because it's using emergency rooms, I believe in every

02:26:41.540 ambulance, you should have methylene blue available. And if there is any insult that compromises

02:26:49.220 metabolic supply to the brain, you're going to be better off infusing methylene blue at a low

02:26:55.620 concentration. We're talking about one milligram per kilogram concentration that is going to be

02:27:02.180 be neuroprotective, regardless of the source. It could be transient ischemic attract. It could be

02:27:08.980 in a stroke. We have done this in a stroke models in animals using the methylene blue. And we've been

02:27:14.580 able to rescue the majority of the damage produced in the infarct in animal models. And animal models,

02:27:22.100 when we look at this longitudinally using fMRI. So we know this works in animals. I've just been unable to

02:27:29.780 convince emergency physicians to start doing this to their ischemic patients. And not only for the brain,

02:27:36.740 but ischemia affecting all the other organs is being also tried in animal models of neurotrauma with

02:27:44.500 the similar benefits. So the problem is there is no interest by the pharmaceutical company because they

02:27:51.780 cannot make money on it. And unfortunately, the NIH is also influenced by, if you're using an old drug,

02:28:00.820 essentially you're repositioning this old drug for these other applications as a neuroprotective

02:28:06.100 agent or more generally metabolic protective agent. They are concerned that their investment is not going to

02:28:14.660 pan out because when it goes to commercialization, you're not going to be able to patent that medication.

02:28:21.220 And believe it or not, even though if it works, if there is no prospect that profits can be made,

02:28:28.020 they don't want to invest. Yeah, it's a shame because I worry that we'll be in this state of

02:28:32.180 limbo where we're not really going to know the answer and we can't know the answer without clinical trials.

02:28:37.700 This is about as easy an agent as there is to study given its long history, its relatively well

02:28:43.300 understood toxicity profile, and in many cases, the speed with which you could see a response,

02:28:48.580 especially if you're studying ischemic events. And I will tell you that just a couple of years ago,

02:28:55.380 it was published last year, the group that I collaborated with in San Antonio, we were the

02:29:00.580 first to show the effects of methylene blue in the human brain using fMRI and measuring blood flow and

02:29:09.140 measuring ball signals. And also in those subjects, we did memory testing and we were able to demonstrate

02:29:16.740 a significant improvement in their memory retrieval just after an acute treatment with methylene blue in

02:29:24.020 a blind placebo control study. The first time that that was done, contrary to these other groups that are

02:29:31.860 doing it as an anti-tao aging in healthy and older people, we can improve memory and we can demonstrate

02:29:41.380 using imaging that we can do this through methylene blue. So the only problem is that there's not going

02:29:47.940 to be any profit because I believe if some company would like to develop this purity pharmaceutical grade

02:29:54.660 methylene blue, there will be a huge market. Other companies may imitate them, but there's enough for

02:30:01.300 everybody. Still, the cosmetic aspect of having urine that is this color is a problem. Many people

02:30:08.980 would not accept it.

02:30:09.940 Yeah. Well, Francisco, this has been great. You've been very generous with your time and I really

02:30:17.380 appreciate this discussion. I've learned a lot and I'm guessing that people listening to this will

02:30:21.380 have also learned a lot. So we will have a great set of show notes to accompany this where all of

02:30:27.300 the papers that we've talked about, a link to Jack's book and a number of other things will be

02:30:32.020 included so that hopefully it's a reference for anyone else you want to share this with and

02:30:36.500 certainly anyone listening. So thank you very much.

02:30:38.500 Thank you, Pete.

02:30:41.700 You can find all of this information and more at peterattiamd.com forward slash podcast.

02:30:46.900 There you'll find the show notes, readings, and links related to this episode.

02:30:51.060 You can also find my blog at peterattiamd.com. Maybe the simplest thing to do is to sign up

02:30:56.180 for my subjectively non-lame once a week email, where I'll update you on what I've been up to,

02:31:00.820 the most interesting papers I've read, and all things related to longevity, science, performance,

02:31:05.700 sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook,

02:31:10.340 all with the ID peterattiamd. But usually Twitter is the best way to reach me to share your questions and

02:31:15.540 comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only and does

02:31:20.900 not constitute the practice of medicine, nursing, or other professional healthcare services,

02:31:25.860 including the giving of medical advice. And note, no doctor-patient relationship is formed.

02:31:31.380 The use of this information and the materials linked to the podcast is at the user's own risk.

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02:31:46.260 condition they have, and should seek the assistance of their healthcare professionals for any such

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02:32:04.660 Both organizations for teaching at thej.com forward slash about.

02:32:09.620 Your domestic power coach has been labeled, as well as an expert in understanding the

02:32:13.860 profession of health

The Peter Attia Drive - January 28, 2019

#38 - Francisco Gonzalez-Lima, Ph.D.： Advancing Alzheimer's disease treatment and prevention – is AD actually a vascular and metabolic disease？

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