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?

Episode Date: January 28, 2019

In this episode, Francisco Gonzalez-Lima, a Professor of Neuroscience and Pharmacology & Toxicology, explains the vascular hypothesis of Alzheimer’s disease which says the central problem is a progressive neuronal energy crisis of impaired blood flow to the brain and impaired mitochondrial respiration. He walks us through the ways we can intervene in this process and also shares details of the exciting future of Alzheimer’s treatment and prevention. We discuss: Background and interest in the brain [5:15]; The unique nature of the human brain [9:15]; Why we’ve made so little progress in Alzheimer’s research [23:00]; The amyloid beta hypothesis [28:30]; Hypometabolism in the brain leading to cognitive decline [39:30]; Early signs of AD, and deciphering between age-related decline versus something pathologic [47:45]; The vascular hypothesis of Alzheimer’s disease [54:00]; The relationship between mitochondria, cytochrome c oxidase, and Alzheimer’s disease [1:08:00]; Chronic inhibition of cytochrome c oxidase leads to chronic neurodegenerative disease [1:22:45]; Major risk factors for AD, head trauma, and other forms of dementia [1:33:45]; Methylene blue for treating and preventing neurodegeneration [1:38:15]; Current standard of care for AD, and the reasons for a lack of advancement [2:01:45]; Near infrared light as a targeted treatment for cognitive decline [2:05:30]; The ketogenic diet as a treatment and preventative measure [2:13:15]; Exciting future research coming from Francisco [2:23:00]; Methylene blue for traumatic brain injuries [2:25:15]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peteratia-md.com.

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My guess this week is Francisco González Lima, a professor of neuroscience and pharmacology and toxicology at the University of Texas, Austin. In this episode, we talk about Alzheimer's disease. In particular, Francisco explains the vascular hypothesis of Alzheimer's disease. A hypothesis that his colleague and collaborator at UT Austin, Jack Bellatory, introduced to the field about 25 years ago. He makes the case that the central problem in late onset Alzheimer's disease is a progressive neuronal energy crisis, meaning impaired blood flow to the brain and impaired mitochondrial respiration. If the problem is an energetic crisis, Francisco argues that we can improve the supply of energy

and blood to the brain, we can probably make progress in the prevention of Alzheimer's disease. We of course get into great detail at about all of this stuff, and to paraphrase my friend and my colleague Richard Isaacson, who I've already spoken with on the podcast a while back, as you may remember, and who directs the Alzheimer's Prevention Clinic at Cornell. If you have a brain, you don't want to miss this episode. So without further delay, here is my conversation with Francisco Gonzales Lima. Cisco, how are you?

Fine, thank you. Thank you so much for making time to see me on a Friday afternoon. My pleasure. This is actually my first time to the university. I've been to Austin many times, but I never seem to be north of downtown. So it was beautiful to drive by the medical center on the way here. It's kind of amazing. I haven't even been to a football game, which I hope to one day do at some point. So how long have you been in Austin? amazing. I haven't even been to a football game which I hope to one day do at some point.

So how long have you been in Austin? I've been here as a ten year professor for 27 years. Wow. Yes, and during that time, I started out in our pharmacology and toxicology and moved to psychology just added that. Then the recruiting institution was the Institute for Neuroscience. And now I'm a faculty also at the Department of Psychiatry at the New Medical School. And we were talking a little bit earlier, you describe yourself as a behavioral neuroscientist. Yes. Tell me a little bit about what that title means.

Why behavioral? My original training as a PhD was anatomy and neurobiology. And then as a post-ocular fellow, I tried to understand how the brain related to behavior. And I did that work as a home of fellow in Germany. And that was my introduction to the study of functional brain mapping and how we could see behavioral functions reflected in brain activity. This was the time where we developed the fluorodeoxic glucose, autoradiographic method in that German group in Darscht.

That later became the key to develop FTG PET, the first functional imaging technique in humans. It's interesting you say that because I noticed that a number of patients when I talk to them don't understand sometimes the difference because I don't think physicians explain the difference between functional studies and imaging studies and I remember feeling very fortunate in medical school during a radiology rotation where one of the residents sat me down and explained the difference. And the pet, of course, the FGD positron emission tomography, being a great example of a functional

study, it's not giving you anatomic resolution, it's giving you functional resolution with respect to glucose uptake. And similarly, you now have functional MRI, which is doing the same sort of thing. And so yeah, that's a very important distinction. Especially important, if you want to be able to determine a disease in a very early stage, in which there are no stroke or changes in the brain that can be seeing at least at the microscopic level.

And having functional techniques, you are able to identify these functional changes even before you have any other signs of the disease. So I know you're a gentleman who has spent time all over the place. You were born in Cuba. You left Cuba when you were quite young. You spent time in Costa Rica, Venezuela. I mean, where did you... Puerto Rico.

And Puerto Rico, of course. All of those things, at what point did it become clear to you that you were interested in the brain? I think my father was a better married doctor. And originally, my interests have to do with working with animals. But soon, I realized the nervous system was so important for the entire health of the animal. And the behavior of the animal, so I started to move away from just a more general interest to something that had to do more with the brain. But I would say my key influence happened as an undergraduate at Tulane University in New Orleans

when one of my professors, Dr. Joanne Keane, dissected a brain in one of our classes. And this was an undergraduate honors class. And it was fascinating to me. And I joined her lab to do an honor's thesis working on the relationship between the brain hormones and behavior in animal models. It's so interesting, I think, back to my own time in medical school. There were clearly a subset of my colleagues who were so captivated by the brain, which in gross anatomy really doesn't depict a fraction of its brilliance, right? Unlike the heart, where certainly microscopically there are things about the heart that are relevant. You can't see the perkinji fibers, you can't see the AV node or the SA node. There's

so much that is invisible to the naked eye, but for the most part, you can appreciate the brilliance of the heart at the macroscopic level. But then there are other organs that, you know, in the other end of the spectrum, get no attention, like the liver. I mean, macroscopically, it's just a lump of whatever. But of course, what's happening inside the liver, to me makes it one of the most remarkable organs. But the brain is an organ that has such a unique look, right? Grossly, it looks so distinct, the tissue looks so distinct from all of the other tissue outside of the central nervous system. And also, to this day, I would say our knowledge of the brain must be far, far behind that of any other organ

at the sort of physiologic signaling level. I mean, is that, I mean, is that a fair assumption? Oh, yes, either agree completely. And I would say using the same analogies that you have, the heart, you can think of it as a mechanical engineer, a pomp, hydraulic pomp, whereas the brain is more of an electrical engineer, where you have lots of circuits.

And the liver, for that matter, will be a chemical engineer, where we break down all of these substances that the body consumes. I actually love that. I've never thought of what you just said, and that is a great way to explain the different types of engineering. The kidney would be some sort of sanitation filtering engineer.

I mean, we could really, yeah, yeah, yeah, environmental. And so in many ways, the brain is probably not only electrical engineering, but it's computer science engineering. It's there's so much going on there. Right. You hit in a very important point. One cannot simply look at the brain the same way that you look at other organs, because of that circuit property, it allows the development of computational power. So the brain uses the circuits, not just for communication, which is the most obvious function, but to determine and compute outcomes that they are used to guide the other tissues in the body.

For example, the musculoskeletal system cannot do anything on its own without the commands that are the result of computations from the nervous system. So all of our behavior results from how the nervous system process our experiences and our current situations and this becomes not in the same way as a computer works, that is a serial device. The brain is a very redundant parallel system where they have to be a lot of convergency between different regions that are computing for that to be acknowledged as the way to go in a behavioral point of view. So for a person listening to this who might not have the luxury of knowing some of the

nuances about the brain that you do, when you're talking to an audience that is presumably most people are interested in the brain because of brain pathology, it's, you know, once a disease strikes the brain, everybody becomes well aware of how much it's doing because the absence of that function leads to such an obvious downside. How do you describe for people this notion of convergence and redundancy and overlap? I mean, obviously, there's a very strong evolutionary reason. What are some examples of those and how those things are, these processes are preserved in terms of, because you use, I like the use of, I'm an engineer, so I do like the use of talking about serial versus parallel processing. Maybe expand on that a little bit. In reality, all of the anatomy is redundant and parallel. For example, we have bilateral symmetry. You know, everybody knows we have two hands, two legs, two eyes.

We probably could have done it with one eye, but the way the system works is that it creates redundancy. And for example, the circulatory system is the same. You have parallel blood vessels where you can get the blood from one point to another in more than one way. And of course, when you sit, when you put your elbow down, you can compress a blood vessel, but there is still another route that can be used. It's like coming from the university to the downtown area.

You have many options to get from one point to the other. So in the brain, this is maximized to its extreme, is an organ specialized for this large amount of communications, in other words, having so many highways and avenues where information can go through. So in that sense, differs from other organs where you have a pattern that repeats itself. And the redundancy is only on that pattern. Here in the brain, the redundancy is combined with the acquisition of new networks or circuit auctions. There are no possible if you only have one design. So you have multiple designs.

If you want an analogy, for example, when NASA was sending the man to the moon, they have like a hundred computers doing the same computation. And then they look at the output and they see which is the output that is repeated more often. And that's the one that those coordinates are the ones that they're going to pass on. The brain uses that strategy and that's what I mean by convergency. In other words, you have all of these multiple parallel systems and they are doing these computations, but only the ones that converge on the same solutions are the ones that are acknowledged and move on for the next stage. And when you look at other species beyond humans, how much of that redundancy do you see as

you go down the evolutionary chain or down the food chain, maybe as an easier way to think about it? I mean, at what presumably, you know, chimps and cats and dogs are very similar, but is there a point at which it very suddenly stops or does it simply diminish to the point where, you know, when you're looking at a simpler organism like a worm, for example? I don't even know what the which it very suddenly stops or does it simply diminish to the point where, you know, when you're looking at a simpler organism like a worm, for example, I don't even know what the nervous system of sea elegans looks like. Well, definitely mammals and primates, in particular, where basic plan is the same. And most of the differences have to do with which of the networks are more developed than others.

So in primates, we have the cerebral cortex becoming the dominion, component in the brain. This is to a certain degree the same thing in all the mammals, but then all the regions of the brain have more similar contribution. When you go down to, for example, reptiles or amphibians, the midbrain, the mesencephalum is the largest part of the brain, not the portion where we have the cerebral cortex. And what that means basically is in addition to this parallel processing that we have, information goes through several hierarchical stages. And at

every one of these stages, similar processing is done. And you add an additional piece of information when you move it on. For example, you can respond at the level of the spinal core that will be the lowest level of response. That would be, for example, a reflex. Like if you tap somebody's knee, you transiently lengthen the patellar tendon, the knee kicks out to straighten it or reduce the length. And that is happening outside of the brain. Yes. However, when you tap the knee, the information also goes to all the levels of the nervous

system. In that case, you saw the spinal reflex be manifested. But the person still knows they felt the sensation and they know what happened. So the same was happening at a different hierarchy level processing. So, behaviorally speaking, when we respond to stimuli at a very basic level, like you indicated, like the spinal level, we call it a reflex. So, we, the most basic behavioral response. But that means that you are not seeing what is happening at the other levels. But, for example, in a frog that is following an insect, the worm has its moving, the frog with orient

to the movement. As long as the worm is moving in the same direction as the long axis of the body, you have the same worm that is a fake worm, where it is moving in a direction perpendicular to the long axis. The frog will not follow. So the pattern isn't recognized. So if a frog sees a worm moving in the normal direction of worm moves, it knows that pattern. If it sees the exact same food source standing up and walking on the side, it's not going to pursue it. It's not pursuing it.

So, but in order to do that new computation, then you need the level of the midbrain. So the midbrain becomes now the point our decision is make and whether to follow and then eventually snap and capture the worm. So the Sugma Malian species primarily operate at that level. And they have well-defined, instead of being called a reflex, we would call this like release stimulus. Release stimulus creates the generates a pattern. There is a pattern generator that recognizes it. But then in mammals, we have to move information

to the level of the thalamus, that is in the middle of the brain, but I get done the midbrain and then from there the majority of the mass of the brain is in primates and humans in particular is in the ciliracortex. So we have to pass that information to the ciliracortex and then feed that back down to the output systems. So it might be a way of oversimplifying, but one could think of it as the brainstem and spinal cord are responsible for these reflexes. For example, we breathe without thinking because our brainstem allows us to, we recoil

from pain without thought because of these things. The midbrain took it up a notch by basically allowing for that stimulus response, but the thalamus then becomes the gateway to the cortex where we can do this higher process. That's probably an oversimplification, but... And the main contribution of this thalamacortical system is to allow us to inhibit behavior. In other words, not to respond in a more immediate short term matter. So they really did to delay a response and to try to compute what are the consequences if we were to make that response. This is where

really is brought up by our more elaborate cerebral cortex. So the majority of the influence of the cerebral cortex on subcortical levels. It's inhibitory. It's not excitatory. No, and engineers actually don't stand this very well. When they, for example, try to create a prosthetic device to have somebody send never-reliant pulses to move a leg that is paralyzed, they try to create this as an excitatory type of phenomenon. But what the brain is doing is not like that.

What the brain is doing is inhibiting all possible vectors of movement in a space and then selectively releasing some of them by sending an inhibitory signal to that. Yeah, it inhibits the inhibitory signal thereby selectively quite a low releasing activation. Yes. And when you do that, you have more control. Because you are actually for every movement, you're not just working as a puppet where you are trying to only emulate those vectors.

You're controlling all of the other possibilities. So you sort of curve a tunnel in a space, which are the only vectors that are allowed to be manifested. So the engineering of the brain in this sense requires this more effort in order to achieve something that could be achieved by a more simplified system because it wants that control. So is it safe to say that more of the pathology that we see in the brain occurs in the cortex than in the midbrain? For example, Parkinson's I guess would be partially midbrain, right?

Primarily. Yeah. Are there other great examples of common pathology in the brainstem? Yes, but from the point of view of the mancha and neurodegenerative disorders with the asexion of Parkinson's disease, these are primarily cerebral cortex. This is where you see, especially the initial functional deficits, and later on, the atrophy and loss of tissue. But most of the diseases of all age that affect the brain primarily target these cortical regions. And that's obviously the thing that I most wanted to chat with you about because you and your colleagues, you have a different point of view on Alzheimer's disease. And in many ways, it's when you, you know, read your work or hear you guys talk about it, it doesn't sound that hard to believe. It's actually quite a reasonable hypothesis.

Let's start with the conventional thinking on Alzheimer's disease, which needs to be caveat with the fact that there is no disease for which we have had a greater failure in our ability to treat it than this one. Even cancer, which one could argue were not exactly hitting it out of the park on, we at least have some success. We can point to very, very specific successes, not only in terms of prevention, for example, simply the recognition that something like smoking could cause cancer, led to an enormous reduction in a continued enormous reduction in the onset of that disease, but also very specific hemotherapeutic regimens for a subset of cancers, particularly liquid

cancers, and now more recently we've seen some real breakthroughs with things like checkpoint inhibitors, uneven solid organ tumors. So at least with cancer we have some sense of we're making progress. Certainly with heart disease we've probably made the most progress. And yet with this disease it appears we have not made a shred of progress. What is the typical explanation for what causes Alzheimer's disease? And therefore by extension what the path should be to prevent it or treat it. You're completely right. We have not made any significant progress in Alzheimer's disease research.

This is the largest failure of the biomedical research enterprise in the world during my lifetime. And the main reason is we have remained faithful to an initial observation that was done or published a lesson in 1907 by Louis El Simons that indicated that he saw this abnormal deposition in the brains of an individual after that individual die. This individual was 51 years old when he died, but Alzheimer's was actually a psychiatrist. Not an aeropathologist like his pointed out in books. He worked in a psychiatric hospital. It was part of the original group led by Crepling in Munich. And they were studying mental illness. And in those days it was believed that what we call now is dementia, it was a form of mental

illness. And he was surprised by this John patient that was showing these early signs of dementia, you know, in his 50s. And already by the time he died, that person has been suffering for many years. So what Alzheimer's describe in the brain of that individual has Alzheimer's disease is not the same disease that is happening in older people. It's not the same disease that is the most common type of dimension. And this is being the most basic misunderstanding from the beginning. Historically, there was a competition

between two groups, one in Prague and Czech Republic, but that time was under German rule. And Oscar featured published studies where, for example, he looked at 16 brains from patients ahead, what was called senile dementia. That is the type of dementia that was showing up in people after they were 60, 70, 80 years of age, not this younger individuals. And he described some of these same abnormalities that later that Alzheimer's published, but for that single case. However, Cripling was a rival of that group, especially about a feature who was Jewish. And so he published in the first book that talk about Alzheimer's,

the first textbook of psychiatry that was published by Cripling, and then he said, oh, what we're seeing in these old people, this type of dementia, is what Alzheimer's is, is cry in that younger individual. And from their own, there was a movement away from factors that were related to aging and to say this is a disease that is in badin somehow and it's not something that is building up over the years. Of course this is actually not the case. So nowadays they try to have a compromise and say Alzheimer's disease, there is early onset or familial, which is primarily familial.

There is some evidence for inheritance, but nine out of ten cases of what is referred to as Alzheimer's disease, there is absolutely no inheritance or familial component, which is one of the greatest fears of people when they have patients with dementia in their family. And not only that, it's aging-related, and because it develops very slowly over the decades, it provides an opportunity to intervene, to determine what are the risk factors that are behind, and to do an intervention. If you take the other approach that this is a disease of these abnormal proteins and it can happen early

on, then you have a very different strategy. So, the whole field has been dominated primarily by what is called the amyloid beta hypothesis. This is hypothesis completely, absolutely false. It has no relationship whatsoever with what we see in the older people that develop the mancha. It has a relationship with some of these early cases that like the one that Alzheimer's is derived and the have a familial component and that there is a somatic genetic component. Let me just interrupt for a second to make sure I'm understanding this is obviously such an important point that I want to make sure I'm I'm clear in that the listener is clear. Now the case that Alzheimer's found in 1907, I have to assume

that was a PSEN one or two mutation. That was what we now see accounting for less than 1% of Alzheimer's disease, but it is probably the closest to a fully penetrant gene that results in Alzheimer's disease. Has that ever been confirmed? Are there any biologic specimens remaining from that particular individual who was so young? There are slides available, but it has never been confirmed. And the patient died in 1906, after many years with this chronic dementia in that hospital in Munich. And he was deteriorated in every other respect by that time.

He was unable to move and carry on on activities of daily living. So he's been suffering from these for many years, which is not unlike what we can see in the rare patients that do have the PSEN one or two gene, which is it can easily take hold in the 40s. I unfortunately have a patient whose mother is, you know, debilitated in her mid 50s. Now it turns out she doesn't have the gene,

which was a surprise to a lot of us. We assumed because it had taken hold so early. But the autopsy, the pathology that they could see, which at the time was limited to very gross things relative to today, gross for the listener. I don't mean gross as in disgusting. I mean, gross as in visible through a microscope. Was this the first time that emaloid beta was observed? No, the first time was done by Oscar Fisher in the senile dimension.

So Alzheimer's was basically describing a phenotype, but without a pathologic explanation or characteristic? Yes, but because it was happening so early, then it moved the people away from the idea that these actions do with senility, with the older deterioration that happens, the function of aging. So they say, oh no, this can happen early on. So aging cannot be a primary contributor. So even though a very small percentage of people that are described as having Alzheimer's belongs to this early onset over 90% of the research is focused on that group. And the reasoning is because it's the same disease, which is a false premise.

If we find out what's happening in the early onset and we model that in animals by doing this genetic manipulation, then we can fix the more common senile older age, late onset dementia. And that false premise is what is being driving all these failures. Because yes, they have been able to detect genetic changes. They can manipulate this. I was able to work, examining the brain of the first amyloid precursor mouse model that was developed. And one of the first things that I noticed in the brain, even before there was any amyloid deposition in that model that they had inserted, they had, it was a transgenic mouse model, they had taken away the native gene

from the mouse and replaced that gene with one that was abnormal for an patient with early onset Alzheimer's. But even before that gene could start any observable deposition of amyloid, these brains by that very manipulation were abnormal. They had severe atrophy. In, for example, the corpus callus of the bundle that communicates the two hemispheres and the region of the hypercampus formation has lost one-third of his volume. So the intervention itself may have altered the resilience if nothing else of the brain. And of course, then these animals show all kinds of behavioral abnormalities. But these things were happening even before there was any amyloid deposition.

So it was clear that having a gene with these abnormalities, even before you can see that product building up is enough to distort how the brain develops. So this is being the main problem. And because biology, just like when I started studying biology, my major was called cell and molecular biology, and that became the dominant orientation in biology. So, people who do this research oftentimes don't have a very good understanding of the brain as a whole. And they just focus at that molecular level. And in a way, they are trying to find the answer with the light that is the light that they can use, and trying to ignore that this is really a disease of all age that involves a long development, and that there is absolutely no correlation,

no relationship between the amount of, for example, Amiloi Beta deposition, and the onset of memory deficits, cognitive impairment, or the progression of the disease, there are brains of individuals that I have the fortune to examine here in Austin, has ham from all year, neuroanatomies, a functional neuroanatomies, I collaborated with the neurobathologies here. And the brains of these people who were cognitively normal, after they die, they could have differentiated them from the ones that were diagnosed as self-simons, basing amyloid and neurofrifularitangal deposition.

That's an enormous statement. It doesn't call into question the causality of amyloid. It just calls into it the necessity and sufficiency of it. In other words, it could be that you have to have, I mean, I'm making this up, but to illustrate it at a point within logic, it could be that you need to have amyloid beta deposition to call dementia, but that is not sufficient. It is only a necessary condition and that you might need other factors to coalesce around that the obvious example that comes to my mind is LDL and APOB, which is necessary for cardiovascular disease, but not alone.

So, fissions, you still need an inflammatory response and an immune response. I go beyond that point. What I'm saying is against the dogma. You're saying one step further than that. You're saying that not only is the deposition of amyloid not correlated strongly enough, it might not even be causally related. Not even it is not related to what we call Primarily Alzheimer's disease with this this majority of late onset

That's not true for the early onset. What I'm saying is that there are two different diseases. The early onset, there is a role. For example, with the position, you can demonstrate this. In other words, if you take autopsies of 50 year olds that die from heart disease, cancer, or accidental death and you examine their brains relative to 50-year-olds who die from early onset dementia, the relationship is more clear that the... Oh, it is clear. The M.O.I. beta is playing a causal role.

Yes, there is no question, and you can find the genetic mutations, and you can induce it in the animal, but that's not the case in the late onset. And the neuro pathologies will tell you, if they don't know what the clinical picture was, they wouldn't be able to say that this was what they refer to as a probable Alzheimer's disease. So when they see the sac to the same pathology, and then there's no evidence of cognitive deterioration, they just diagnose that brain as possible Alzheimer's disease. So this created a circular definition.

To be clear, to close the loop on that analogy with heart disease, you would have to know that there are cases where patients have significant dementia that by all other metrics is consistent with Alzheimer's dementia, not Lewy Body or something else. And there is absence of amyloid beta deposition. And what percentage approximately, I know it's hard to know these things because we don't always get autopsies, but in your experience, what percentage of patients

who die with or from Alzheimer's disease that is laid on set do not have the histopathologic features of emoloid beta? The majority of patients that are diagnosed as Alzheimer's disease, pro Alzheimer's disease, when they die, have the same level. It's not that they don't have, because this is an age-related deposition. The same levels of other patients are a comparable age. And the only reason that they are a label of Alzheimer's is because they had dementia. The pathology cannot really tell them apart. If you give these two pathologies blind to the medical diagnosis or clinical examination, they won't be able to tell apart which are the ones

are actually the minted and which are not. If you do it in a match, there is a large degree of variability and pathologies are not quantitative. Pathology is an approximation. You look at only a few sections through the cortex, and then you give a certain proportion of the findings that you see as categories. But even when I have done this personally, in 2001, we published in the Journal of Neuroscience a study where we use brains from people who die from Alzheimer's.

The main difference from my study from what's been done before is that we were able to obtain brains. We'd only have few hours after the individuals had died. We call the very small post-mortem interval. And I was able to do this by collaborating with the institute in Arizona. There is a city called Sun City Arizona and they have a Sun City Health Center which actually ascribes to this army law and theirary dangle ideas. But what we did with them was, we traveled there

and with my PhD student, we collected these brains, control brains and brains of people who have that diabolism. Some of them we were able to collect them fresh right there. And were you and your team also blinded to the circumstances of the death prior to the autopsies being performed? No, what we did is we collected all the brains and they were ice sectioned them into pieces and these pieces then were frozen and then one sample would remain

there. I see, I see, I see, know that everything in parallel. Yeah, we'll be chip here to Austin. And once the samples were chip, they were coded. But when we were there, not we knew when somebody died, because I had a pathologist with me who had to certify. They were there so that we could immediately. But when the the-wise results were evaluated, the evaluator was blind to the clinical circumstances of the patient's death. Yes. What we did in that study was we were not only interested in just looking at amyloic plates and neurofibular retangles been done. We were interested in seeing, is there any biochemical change that could account for this so-called hypometabolism, this decrease in energy metabolism that is seeing early in Alzheimer's?

Is it generally well regarded bringing it back to some of your earlier work in PET? I assume it is generally agreed upon that patients who are in the stages of cognitive decline have hype O functioning metabolism. So their PET scans show less glucose uptake in the brain. Is that generally acknowledged? And not only FDG PET, when you do also Cidri blood flow, you find the same. When you do FMRI, there is spin labeling to look at blow flow. You find the same. When you do FMRI, your tedious spin labeling to look at blood flow, every technique that have been used has demonstrated that first it was with mild Alzheimer's cases, but more recently also with them so-called mild cognitive impairment that nowadays they're also referring to as mild neurocognitive disorder. And in those cases, there is hypometabolism.

And the hypometabolism is primarily not in the regions that become a traffic. Later on in the disease, like in the temporal lobe, it's primarily in the posterior single-acortex, one region of the brain that is in the medial bar in the center of the brain. This area is the one that you can see having early a sign of hypometabolism.

And from a phenotypic standpoint, what does it control in the normal brain? This region provides the major input to what is called the Enterrinal cortex, which is the part of the temporal lobe that then feeds into the hypochampal formation. So what essentially is happening is you have a functional disconnection between the main input to the entorineal cortex. The entorineal cortex is the primary source of inputs

to the hypokample formation. So when you functionally denervate a region in the brain eventually that leads to atrophy from that region, that it is receiving the stimulus. It is receiving that. Just like happens when you denervate a muscle in the periphery, there is a trophic action and action that that region survives because it's being stimulated by the other one. So people have missed when you study

pathology, you don't study these functional changes and you don't look at the system as a network of pathways or influence functionality. You're seeing the end result. What has happened after all of these processes are taking place over the years. So by doing that, you cannot infer these other phenomena. If you take an animal like a mouse and you just take out the, it's the posterior singular. The posterior singular. phenomena. If you take an animal like a mouse and you just take out the, it's the posterior singular. The posterior singular. Yeah.

If you lesion that in a rat or a mouse acutely, which is not the same as what's presumably happening in this disease state, what is the immediate phenotype of that animal or behavior? Well, you don't have to lesion it. You can functionally deactivate it, which is more similar to what is actually happening in Alzheimer's is not that this region is damaged structurally. Right. It's just functionally not allowing the conduit. Yeah.

It's a signaling conduit effect in that network that is providing the main input to the hippocampal formation. You get the same kind of memory deficits that are characteristic to the initial stages of dementia. And is that because of the role the hippocampus plays in the consolidation of memory, or is it to do more with the target in the temporal lobe? It is because it's a network, not a single region. In other words, for example, Lontan Mago in the 19th thuries, there was a circuit that was defined by an American narrow anatomist called James Papis, also pronounced Papis. And he describes the connections between the

single cortex, this parahypocampal cortex that we now primarily refer to as the entorriinal cortex and then from there to the hapocampus formation, from the hapocampus formation, the main output goes to region called the mammillary bodies and then from the mammillary bodies, it goes to the anterior part of the Thalamus. And then from the Thalamus, it fans out the projections back into the single ecortex, so it creates a circle. And this is often being referred to as the limbic circuit of papers. And we know we have to do with emotional memory formation, because events that have a large emotional signature are the ones we store for the greatest memories from them. So, if you affect this system anywhere in this system, you get have chronic alcohol, they develop sometimes, referred to as a Wernicke's Corsica of dementia, also known as Corsica of psychosis.

You can get this from B vitamin deficiencies as well. B1 deficiency, I mean deficiency in particular, you look at the pathology of the brain, where is the damage? The damage is primarily in the mammillary bodies. Well, the mammillary body is the main output from the hyper-pogampo-formation. So whatever the hyper-pogampo-formation is contributing, if you are knocking down his main output target, you get the same thing. Then in a second place is the hyper-pogampo-formation itself,

then the enter under the cortex and so on. All you have damage in any part of the search system. There's also something called diencephalic retro-reamnesia that happens with the lamic lesions, well, this is when these lesions interfere with these anterior thalamic areas. So really, in order for us to see the memory problems that we have linked, usually with Alzheimer's dementia, So really, in order for us to see the memory problems

that we have linked, usually with Alzheimer's dementia, you have to engage the system because that system is part of the brain regions in which this is operating. You use the term retrograde there. For the listener, we should explain the difference between retrograde and integrated amnesia. I'll let you do that quickly, but of course, my follow-up question will be in the

earliest stages of dementia is the bigger issue, the inability to form new short-term memories, which should be a form of anti-grade amnesia. That would happen before the retrograte amnesia, which is later. Let me explain. In the early Alzheimer's disease, the main problem is not in this limbic circuit. When that happens, when you can see the hypometabolism, that's when you can see the behavioral changes in the individual as well. But before that, in the prefrontal cortex, especially the lateral, we call dorsal lateral, prefrontal cortex, you have a functional deficit that is interfering with what we call working memory. So you can think of memories as having three modes or

temporal stages, an immediate memory mode where you can remember things for only a few seconds. Tell me your phone number and I have to write it down. That's correct. That's correct. That's the perfect example. A clinician will do these by giving a string of numbers to people and people will be able to remember approximately seven numbers.

So it is usually seven plus or minus two items. And this is the reason why the telephone numbers have seven digits because most people after reading seven digits Turning around to try to punch those numbers in the phone if there are more than seven They drop some of them is this immediate memory mode But for memories to happen they have to move from this immediate memory mode to a more recent memory mode. So the immediate movement from immediate to recent is done by this prefrontal cortex. So the initial deficit that you see in Alzheimer's and all of these types of dementia of all age is in this more immediate memory. And one way we refer to this is also working memory. So, for example, you come out of your house and you lock the door, but after a few seconds

you're working to your car, then you ask, did I lock the door? Or is it on lock? And then you have to go back and check. So this is the first thing that you're going to have. Any happens physiologically as a function of aging. And this is the first one, this working memory things are. So the prefrontal one is the initial signal that there is a memory probably. This is before and this is an anterior rate memory. In other words, it's a new memory that you want to form.

So this is the first thing that is affected. But once the memory are in the recent memory mode, this, for example, would be your phone number, which is one of the easy seven digits to remember, because you're so familiar with it that it's now become quote unquote permanent memory. By repetition, by exposure to the same items, this reverberate in that limbic circuit that I just told you, and the hypochampo formation, has an inner circuit that is crucial for that. So it is crucial for that forming, and then you will be able to retrieve that number again. So when that circuit becomes engaged at any point, then

you start having this retrograde memory problem. You cannot remember your number. Which is interesting. That's the point at which the family members tend to really notice what's happening. You become concerned. Yes. But the patients tend to become concerned much sooner. The patients become concerned with the integrated memory deficits. You are absolutely right. How do you distinguish between something you said a moment ago, which was this slight deficit of formation of new memory

is on some levels not necessarily a pathological finding as we age. But how do we differentiate between the pathologic or the appropriate age-related versus the potentially, you know, the harbinger of something pathologic. It is difficult to draw the line. This is one of the main reasons that this diagnosis of mild cognitive impairment has been elusive. I have asked this question to all the researchers and I get very many different opinions. And the main reason is that the only way to know for sure is to compare this to your own history, to compare it to yourself. So in this case, the patient and their immediate patterns, they are more knowledgeable whether they're being a change. If you just compare to a standardized age population, you may not see any difference, but the patient will tell you,

no, I know I have more difficulty with, for example, this working memory task. So, it is a challenge, but the beauty of this is you don't have to wait because everybody goes through this cognitive decline, it's just a different extent. And we all start out at a different level of cognitive performance. So it's very difficult to have a standard. So my approach is to try to intervene at that point. And therefore, the main target at that point is to intervene in the prefrontal cortex, the region that is just behind your forehead.

And that one engages, we call a central executive network that for cognitive processing that is involving working memory, that is involving problem solving, that is involving sustained attention, vigilance, those are the things that you're going to be seeing first, having a decline as you grow older, just like all kinds of tissues, decline as you grow older. This is a reality. But it is possible to intervene then before you get into the limbic system, problems, and that's the approach that we have done

and in our interventions. And I think this is going to make the biggest difference. So let's go back to now the sort of revised hypothesis. If I can summarize, the actual nomenclature of Alzheimer's disease might be a bit of an unfortunate artifact and that it was first observed in a subset of what would become this disease that really isn't representative of the epidemic that we're seeing today. Absolutely right. And so we'll put that aside for a moment because despite how tragic those early onset cases are, and they strike me as among the most tragic things I've ever seen in medicine, by the way, you have more experience with this, The thing that's running a muck right now is this sort of late onset dementia that it seems

to me that we are probably diagnosing it much more than we were before, but it also seems to be increasing out beyond just the rate of diagnosis. And it also seems to be increasing at a rate disproportionate to the increase in our longevity, which is really not that significant I believe that human longevity is increasing at about 0.4% per year in the United States and yet the rate of Growth of Alzheimer's disease is growing much more than that So if you discount that somewhat for the rate of for the diagnostic Acumen or urgency with which we seek it

There's still a gap which means on a real level not just a perceived level this disease is becoming more common In your research you talk about five Areas of study that help you think about this the epidemiology of the disease the imaging of the disease the pharmacologic response to the disease, the pathologic findings in the disease, and then the clinical course of the disease. You and your colleagues have a different hypothesis that pertains to the vascular system. Yes. This is actually the original hypothesis that was associated with senile dementia. I don't want to take credit for the people who

gone after that because in the early days it was just an idea, not well formulated, but what seems to be happening is if you compromise circulation to the brain, you're always going to get a neurological deficit. However, in the case of what we're seeing has laid on set the mention that I may refer to as features dementia as both to the early onset Alzheimer's dementia, which is what should be named. There is a chronic hypoper fusion that is the brain is receiving less blood supply. And for example, it is known that between 22 years old to 60 years old,

there is a decrease of about 20% on your supply of blood to the brain. So some people have calculated that approximately half of a percentage per year in statistical terms. Do we have a sense of why? How much of that, I mean, if I think a lay person might understandably

but naively assume that is just due to a gradual and gradual narrowing of arteries or something like that, but it strikes me that that's very unlikely the case and that it's much more related to something within capillaries and or other metrics. Because paradoxically, as we age, we're seeing an increase in our blood pressure typically. So when your 20 versus 60,

you're generally running with a higher blood pressure. So if anything, you would think that should increase cerebral perfusion, not decrease it. But of course, we're not seeing that. So what do you think at the level of vascular biology would explain even that observation? Yes. Unfortunately, the answer is all of the above.

In other words, the vascular changes happened at the microscopic and microscopic levels. But it is the case. If you, for example, only look like we have done, for example, the carotid artery, the one in the neck that supplies the blood to the head, this is where most of the blood is going to the brain from this. And you can use ultrasound, imaging, non-imbaisively, and are able to look at the layers. So even the intimal thickening of the carotid artery, which would presumably get a little more and more and more as you want ages, is going to play a role in this potential.

Oh, yes. There is a linear relationship between what we call the intimate media thickness, the layers of the artery and the decline in cognitive function. Now, why, I mean, the sense silly, but why in linear relationship, given that it should be non-linear, shouldn't it, given that with increase in intimal thickening, you would see exponential change in diameter or in cross-sectional area, wouldn't that lead to a non-linear change in perfusion? No. Which I realized you were talking about cognition, not perfusion, but not perfusion.

The reason there is not a linear change with profusion is what you alluded to. We have an outdoor regulatory mechanism. Has I get it that basically can start to auto correct at least try to dampen it to get dampens it from an exponential problem to a linear problem. That's a beautiful, beautiful example of biology. So has has the art. It becomes stiffer with a linear problem. That's a beautiful, beautiful example of biology. So has the artery become stiffer with the thicker walls? It's just like if you imagine somebody having a hose that is releasing water and then just take your finger in front of the hose and you can see how the water is coming in a faster place. So this is one aspect

that, but this is the outer regulation. The body is trying to achieve that. It does that when the walls become stiffer because of the thickening. When you have this systolic pump that they are supposed to comply or trigger compliance, they don't do that. So even though you may see the lumens being the same size, in other words the hole being the same size, but it's not the same size when you have the pulse, the Volus of blood going through that it has to open up. However, when we increase blood pressure, we have a constant process of trying to increase blood pressure to maintain that same level of perfusion. This now leads to problems with the capillaries because these capillaries

of the compensation for the macrovascular disease may actually be driving part of the damage at the microvascular disease. You're pushing now with a higher blood pressure through capillaries and this creates a pathology at this boundary we call the endothelial walls. And these endothelial walls are now subjected to mechanical pressures that they were not designed to do. And you have extravacation, and you have cells that normally are only engaged when we have, like a hemorrhage, like the platelets to try to coagulate. Now they start sticking to this endotilia walls and compromising some of the micro-circulation as a consequence of. So the auto-regulation cannot compensate and it creates additional problems as time goes by. And that's why you are actually better off with less blood pressure by controlling your

high blood pressure than with more, even though you're trying to make up for the decrease blood supply. And this has actually been borne out in very recent clinical trials. Every five years or so, we see more and more data revising how we think about blood pressure regulation and the most recent results seem to indicate the best outcomes occur with a systolic blood pressure below 120 millimeters per mercury, a diastolic below 80. Formerly this used to be 135-ish, over 90 was accepted.

So that's a significant difference because many people walk around. many adults walk around with a blood pressure above 120 over 80. You're right. And that is an index of this pathology that is developing in the large arteries like in the carotid here, but I'm using the carotid as an example. When this happens at the level of the carotid, you know it's happening up to vertebral arteries and into the circle of willis and the main. Basically, it's happening more in the arteries that have the largest flow, because we get like about one-third of the blood going into the head, primarily for the brain function.

So there is a much more blood flow that is going through those arteries than the one, for example, going to your arm, your brachyl artery. However, in the case of the heart, the same thing happens. You have the small coronary arteries that are feeding the heart itself as soon as you pump. So they have greater flows. And the other thing that happens, these walls are only thicker, but they become irregular, especially the inner walls are no longer smooth. And when they are no longer smooth, you start creating turbulence. That is, if you look at the flow of liquid, when they hit an irregularity in the walls, there is a little turbulence. So, these turbulence creates a system in which the position is going to be favored

like when blood is going or in the blood. That is usually the white blood cells. Is it usually a macrophage that infiltrates as well? Yes, but even before infiltrating, they identified this area of turbulence as an area of a preventory injury. And they started aggregating there. And because of the turbulence itself, they started dying out against the walls. And unfortunately cholesterol levels then can add to it. But they are not the problem. The high total cholesterol is not the reason. Again, they're confusing causality here

with a consequence of this problem. So lowering your total cholesterol is not gonna really make a major difference in this progression, which is, I think, one of the biggest misconception that is happening in medicine right now, but in any case, you have a number of phenomena that are taking place, that are contributing to the ascolar hypoprofusion. On the other hand, you can have a similar type of insult to the brain,

not coming from this atro-sclerotic process, if the heart muscle itself is compromised in its function, because a process where it weakens its ability to operate as a pump, you're going to have hypoprefusion that is going to be developing. And in that case, there would even be less likely that you're going to have an auto-regulatory mechanism for that. So you can have hard disease that is affected the pumping, you know, the force of the pump that can lead to the hyperrefusion. You can have arterial disease like arterous gloruses that is causing similar kind of phenomenon with some more complications that are detected by this high blood pressure. In the cardiac case, you will not see the high blood pressure,

but in the other one, you will see that. And so all of these things can be detected. It is possible for cardiologists to advance and measure these things. And once you detect this, the health of the heart and the arterial circulation in particular is very closely related to the health of the brain. So if whatever you do that improves your cardiovascular health, wealth also helps the brain. But there are some differences. For example, the brain in some ways seems a little bit more exposed

because the brain is profused during systole at a higher pressure. The heart is the only organ that is actually profused during diastole. So in that sense, the coronary arteries themselves are less susceptible to hypertension than the arteries in the brain or the kidney for that matter which would be the two organs that seem to be most damaged by hypertension, more so than the heart. The other thing that I'm hearing you say that creates a bit of a differentiation between the heart is, you know, in the process of atherosclerosis in the heart, cholesterol does play

a very important role, but so you still have the initiation of the endothelial injury, which is necessary, but once the lipoprotein can get inside the subendothelial space and becomes oxidized, that's what elicits the immune response, which is what does the damage. What you're describing in the brain is two different processes from hearing you correctly. The first is cerebral vascular disease that leads to strokes, occlusive or hemorrhagic, which that's a separate disease because it tends to produce an acute event. That is the result of an acute hypoprusion that usually produces a much more functional deficit.

So it's almost like you can think of, that is a quote unquote brain attack, the way we think of a heart attack. Correct. But what you're describing that is now sort of unique to me is a different type of much more indolent, chronic hypoperfusion that actually seems to have a slightly different path of physiology from coronary physiology. Yes.

That doesn't produce an acute event, but rather a chronic disease. Is that, am I, did I summarize that? You summarize that really well. It is this chronic brain hypoprefusion regardless of the particular cardiovascular cause. Because I told you with heart failure, you can have, you can simulate that aspect without some of the other components. So it is possible nowadays to pick this up and to intervene to try to resolve this Baskular problems or cardiovascular they involve the heart so the epidemiology

States the first and most obvious relationship, which is so obvious that it's not almost not helpful Which is there is no greater association with Alzheimer's disease than age just as there is no greater association with cardiovascular disease than age. So that's stating the obvious, but it's very difficult to draw a clear hypothesis or at least confirm a hypothesis. So the next layer of thinking on the epidemiology is what? Is it the association with hypertension, or is it the association with cardiometabolic disease? How do you then continue down that line of thinking on from just just again before we get to the more interesting stuff, which I think is the pathology and the pharmacology just based on the epidemiology, what else can you infer? What would be ideal to me would be what is the main purpose of that circulation from the point of view of energy is to bring oxygen

to the tissue, tissue oxygenation. It is only through this process of reducing oxygen to water that in mitochondria, this process is linked, this cellar respiration is linked to the production of chemical energy. So the more direct measurements would be measurements of oxygen-consumption, but also could be the enzyme that is responsible for that oxygen-consumption. And that's where it comes to our work and what we found in the brains of those Alzheimer patients. We found that the M-SIM calls cytokromoxidase or cytokrom C.

Oxidase. Complex for in the electron transport chain. The electron transport is the last, the last and the rate limit in M-SIM and the one that actually reduces oxygen to water that is linked to oxidative phosphorylation, the creation of ATP. Let's pause for a moment to make sure people understand this. It's so important that even though I think I've talked about this before, it's worth re-iterating. The mitochondria has an inner and outer membrane and these have four complexes. Three of them span both the inner and outer membrane, I believe it's one, three, and four. Complex two is only on the internet membrane. These things are about the most essential elements of life.

Interrupting their activity for even moments at a time is the end of life. I would say is the key to aeroic life on the planet. Yeah, you can't overstate the importance of the electron transport chain. As you point it out, it is basically, yeah, we can't create energy out of nothing, we simply change its form. And so when we eat food, we're eating stored potential energy that is in a chemical form that is generally between the carbon, carbon, carbon hydrogen bonds. As these things get reduced to simpler and simpler molecules, this process, specifically

within the mitochondria, takes these units and it, by breaking apart the chemical bonds, creates an electrical gradient by shuttling electrons outside of this membrane as they go from complex one to three. And of course, they're, each come with their own reducing agents. I spend my most time thinking about complex one, which is the NADH, NAD shuttle. But I believe complex four is NADPH, isn't it? Is that what it's using as the electron acceptor donor? Yes. I need to emphasize from what you're saying.

So people understand the whole purpose of that chemistry that is done with the foods that we eat is to generate electron donors. Electrons donors are going to donate their electrons to the electron transport. And there are only two of them, the NADH and the FADH. And the NADH primarily, it donationsates two different parts of the electron transport system, but the other one, the FDH only to complex two. So you have like two entry points, complex one and two, and then- And that's why complex two doesn't span the full membrane. It's sort of sitting there only on the other one. And it's much smaller than complex one is the largest one. So this is a key.

This is a biochemical key to this phenomenon because what we eat from an energy point of view, it just becomes an electron donor. So it's, can we donate electrons to the electron transfer? If we could do that, we can accelerate respiration because the ultimate electron, a sector in nature is oxygen, and that's what we call oxidation, the process of removing electrons. And so making water out of oxygen, and these protons that are being donated is the ultimate bi-product of respiration. That's why we breathe out water vapor.

And of course, all of this is in service of creating an electron gradient to then fuel the generation of identity and triphosphate ATP. Yes. What they might have done is coupling this affinity of oxygen to take these electrons that are coming from the food that we eat into a closed system in which the electrons, when they are moving from one complex to the other, they are releasing what is called a proton that is positive recharge. And this is trapped in that intermembrane between the two membranes that you mentioned the outer and the inner one and the Matrix of the mitochondria the more inner most portion is primarily negative in electrical charge ions are negative so

These protons are trying to move they are attracted towards this Negativity just like when you have the poles in a magnet, the positive and negative ball, is what we call electromagnetic force. There are only very few forces in nature like gravitation, and this one is electromagnetic force. So the system was designed in such a way that the protons will leak through a hole, and that hole or pour is this complex five and complex five is designed so that when the Proton is pushing through to get from the inner excuse me from the inner inter intermembrane space to the matrix it clicks Changes the confirmation of that enzyme and that movement generates the energy

for a phosphate to be bound to ADP. And that phosphate is called inorganic phosphate when this is what in chemistry is called an endotermic reaction. It needs energy in order to happen and it's because of that movement. And then later on when you need some other enzyme to work, all of these chemical reactions have to do with life are catalyzed or mediated by enzymes. What this means is that you may have the reactants already in place, but nothing is going to happen in terms of products unless you provide energy to the system. So these are so-called

reaction that when you remove that phosphate from the ATP it generates heat. And this is what we call calorie. And you can then have a relationship, but when it is a relationship with how much food you eat, how many electrons are donated, how many of these phosphates can be broken and generate a heat. And that heat is just like in chemistry when you have your reactants in a beaker and you have a catalyst and nothing was happening and then you apply heat and then all the salt and reaction happen, it changes the gallbladder, for example. And when that phenomenon happens, then we call that an exotermic reaction that breaks it and it fuels. So the key to the system

is to be able, how can we facilitate the mitochondrial respiration? And this illustrates, of course, the most important point here, what you're saying is the whole purpose of eating is to convert chemical energy into chemical energy from one form to another. But to do it, you need an intermediary to translate, and that intermediate has to turn the chemical energy into electrical energy that then facilitates a conversion back to chemical energy. That is the key to life, and that is what the mitochondria do. How I would, there is a way to it. At least aerobically, we can obviously do this.

I'm inefficiently an anaerobically later, but yeah. Correct. Correct. You can do these, especially in other tissues, not so much the brain, you can generate ATP without using oxygen and this machinery. But every organism, including single cells on the planet, they use oxygen to obtain energy, relies on cytokromoxidate. They may not have mitochondria, but at least they need cytokromoxidate.

Well, they didn't realize that. So red blood cells, for example, don't have mitochondria. Do they have cytokromoxidate? Yes. I didn't know that. Yes. If they use oxygen to generate ATP, they have to have have cytochrome C and cytochrome C oxidase. This is the minimum requirement.

That's why you can look at cell lines from microbes and zong, and you can identify these proteins. As long as it's aerobic, it's the only way nature found how to solve this. But the interesting thing is that when the circulation is compromised, then you have less oxygen, you're creating a situation where this events can no move on. It doesn't matter how much you eat, and this is happening in older people.

It doesn't matter how much they eat. In fact, their brain is telling them that they should be hungry because they are not able to transfer those electron donors into electron transport and produce energy. So they feel their energy deprived. So they increase food consumption, especially they are attracted to carbohydrates. Simple carbohydrates that can quickly break down and produce these electron donors. So do you think that this is the first insult then? Because you talked about this slightly different type of

microvascular disease that is much more chronic and insidious than doesn't lead to acute changes like hemorrhage or occlusion. How does that change ultimately impact the ability of the mitochondria to do its job and facilitate electron transfer. Yes, put your finger on it. This is where links this phenomena, regardless of whether the chronic hyperperfusion or the more acute, one of the things that happened is when we have a hypoxia situation, cytokromoxidase is an indusible enzyme. What that means is that our body only maintains as much as it's needed, as much as it's demanded.

It's a complex of 13 different subunits, three of them mitochondrial DNA that I've had the other time from nuclear DNA. And you can regulate it at many different levels, including both the nucleus or mitochondria. But essentially within minutes, if for example you have an area of ischemia, you will include a blood vessel, half an hour later you lost a significant amount of cytokromoxides from being...

And that's irreversible then? No, it is not irreversible. That's the advantage of the system. The system works of the system. The system works on the man. It may not be immediately reversible, it depends on the level of regulation. In other words, you can simply inhibit the M-SIME

and the M-SIME is still there. Or you can disassemble the catalytic units of the M-SIME, the ones from mitochondrial origin, and then you have a partial M sign, not the so-called hollow M sign, or you can eliminate the other components and throughout the mitochondrial inner membrane you have all of these gradations of stages that can be used for regulating this. So you can regulate it a more immediate way, or eventually you need proteins transported from the cytoplasm to be chipped where the mitochondria are and incorporating to this. Why was this done? Because mitochondria have a symbiotic relationship with the cells that they live on, and this was created to develop a dependency that mitochondria are doing this, but they cannot do it on their own.

The cell has found a way to obtain the energy, but is conditional on then contributing a component that is necessary for the entire machinery to work. The important portion here is that these phenomena are coupled. As soon as you have hypoxia, it's camea, you reduce. Then this machinery goes down regulated. Is that true of Complex 1, 2, 3 as well? Are they also inducible the way Complex 4 is? Not as much as Complex 4. They are to certain degree if you keep taxing the system, it's going to happen. But the one that has the

more flexibility, from more immediate to long-term, because of this role has very limiting its complex war. And that's the reason it is preferable to the system. That's why I love doing these podcasts. Every single podcast I get to learn something new in biology that I didn't know, I had no idea that complex for was inducible to a greater extent than the others. Has it is, for example, you may have her for sure during your training about other indusible enzymes, the cytochrome systems in the liver. So the liver is... P450, the most inducible of them all.

So it's a perfect example. You know, if you have more talk, if you drink more alcohol, you're going to build up more of these cytochrome enzymes. So these are the most indusible in semantic complexes that we have. You just never think of it in something so important. Not that the liver is less important, of course, but the ETC is so fundamental for everything that we do. It's so interesting to think of that. And it's also interesting to hear you say that at least in transient periods of ischemia, this is not irreversible. No, it's not irreversible. It's an inducible system just like you start

like deliverers, you're thinking alcohol, these enzymes are going to be down regulated, but if you start challenging the system again, they are inducible, they're going to go back. Of course, you're going to suffer somewhat in between because at the beginning, you're not going to be able to meet the demand, but they are inducible. This is the key that I have understood from our investigation of the Alzheimer's brain. In those fresh, frozen Alzheimer's brain, the main problem was cytokromoxidase inhibition. The levels of the protein levels of the M size were not compromised, but you could see that the M size was not in its catalytic functional state, and you could demonstrate this during

and you could demonstrate this doing enzyme histochemistry. If you were able to extract at the moment those patients died, their cells in culture and now they're perfused, would they have still been hypofunctioning? In other words, would you still have been able to measure a deficit of oxygen utilization? Yes, yes, yes. And this has been done, groups have taken,

actually what they've taken is mitochondria. And they can then see that these mitochondria are not performing this cellular respiration from Alzheimer's patients. Give me a sense of what is the magnitude of the deficit to result in the phenotype that we observe clinically? Yes, this is a very good question, because you inhibit cytochromoxidates after about 40% in an organism, the organism dies. You cannot cut.

But presumably it's a nomeogram of duration and degree of suppression, right? So maybe you could have a 40% reduction for two seconds, but not a 40% reduction for two minutes. Or something, I assume there's, yeah. That's correct. For example, the classic poison cyanide. Okay. What does cyanide does? Cyanide is complex for a cytokromoxidase inhibitor.

It gets into the circulation and inhibits cytchromoxes and minutes later you die. So if that happens, it's not compatible to life. However, you can have many degrees of this reduction because the enzyme is so inducible, generally, it changes a catalytic activity of a particular... In other words, cyanide is not binary in its ability to kill. It seems functionally binary because it's so potent that even a trace amount of cyanide will kill. But presumably, if you diluted enough and enough and enough, you could give enough cyanide to somebody that they have a chronic illness. Oh, yes.

Do do. It's almost like it's a thought experiment. You could induce Alzheimer's at a low enough dose of cyanide to create a functional hypoperfusion by inhibiting complex four without killing the organism. And we did this. I like when I think of things 10 years after someone else thought experiment was done. And in fact, Dr. Jack DeLatorre, the one that wrote the book Alzheimer's turning point that I highly recommend.

Yeah, we'll link to that for sure. And we collaborated in that study. So it works both ways. In other words, if you compromise the circulation by partially occluding blood vessels to the brain, you get a down regulation of cytokromoxides. And therefore mitochondrial respiration and ADB production and so on. And the animal, Joe, cognitive picture, that is analogous, it's not the same, but it's analogous to what you see in cognitive, narrow cognitive disorders. And the other way around, you can directly suppress the electron transport.

And in our study, we decided to use sodium asci because it's less button than cyanide and when you do that yes you have an animal that at a very low level of decreasing you can decrease up to 3% without seeing any neurological evident change the animals appear to be eating and behaving normally but when you test them with kind of the tests, they cannot perform well. In other words, a 30% reduction in the oxidative capacity of complex four shows cognitive impairment when challenged, even though behaviorally at the gross motor level, the animal is still fine. Just like an Alzheimer's patient that you will appear, they will appear to be generally

okay until you test the system. Yes, so these animals, and in fact that was proposed as a model for Alzheimer's disease, that very same approach by Collector Mind, the one that comes to mind is Rose Bennett, Rose and Bennett. However, because of the influence of these amyloids and tangles, hypotheses, all of these models were based on biochemical and physiological phenomena where really not developed fully. All the attention was in the genes and the normal proteins. But yes, you can do these in animals. You can test these hypotheses in animals.

Does this lead to any change in the amount? Let's assume you had an animal model where you could do this for a long enough period of time before the animal would die and you had a control animal in which you were not doing this. Would you, in those two situations side by side, see a difference in amyloid beta accumulation? No. The amyloid beta would not be a good reflection of these processes. The amyloid beta is primarily a process that is compensatory when the cells are showing atrophy. So when cells are showing signs of atrophy, we have a lot of amyloid beta that is released

embryonically during the development of the nervous system and it's because during the development of the nervous system, and it's because during the development of the nervous system, you have faces of a large proliferation of neurons, but then you have other faces of trimming, where there is a lot of neuronal death. And in those situations, you see amyloid that is formed. So, as you know, probably the major signal for a cell to die in an aerobic organism is for the mitochondria to release cytochrome C. Cytochrome C is a protein that carries the electron to cytochrome C oxidase. If that machinery is not working and cytochrome C leaks out, we say the mitochondrial permeability

poor has been modified so that small cytochrome C leaks out. That's a big signal for apoptosis. Apoptosis or program cell death. In other words, if a cell might have come to that. That's the surrender of the cell. That's the white flag. Here's where my cytochrome C is. So what I'm telling you is, if you compromise the system,

you're going to have nailed to the generation. You're going to have cell death. And not just in the nervous system, it just happens that there is more critical because in all the systems, we have all the ways to get ATP, but in neurons, we don't have any significant amount of alternative ways to get it. Yeah, that's exactly the point I was going to make is we're having this discussion and it would

be easy for a moment to say, wow, why is this all isolated to the brain? It's not, it's just the brain, I think, has two problems. The first, you know, if you're going to be critical of the brain, the first is an energetic problem, which is it is simply the most demanding, and therefore it is the most susceptible to a reduction in total available energy. The brain weighs about 2% of our body weight and yet consumes about 20% of our total energy expenditure, so that's a grossly disproportionate amount of energy. The second, by the way, would be the kidney, which, by the way, is the second organ we tend to see great ischemic. When we see hypoprusion clinically, we see kidney damage and myocardial damage.

Yes. So the more energy demanding the organ, the bigger the problem. And then the second issue with the brain is this seemingly overreliance on oxidative phosphorylation without an anaerobic escape route. Yes, you are right on target and this is what makes it so vulnerable. And this is why we see these changes more has kind of the deficit before all the tissues are really damaged or the brain itself. But as you continue with this process, as we just talk about, if down-regulation of cytochromooxidate reaches a certain level, cytochromcy is going to start releasing. There is a permeability change, goes out and cells start dying. So it is the direction of causality is completely different from the amyloid ideas that the amyloid

comes there because of the gene that is abnormal and then it's creating these cascades that are leading to these changes. No, what we have is these problems with supply of oxygen that happen to the brain and it's this high energetic demand and they could be due to the circulation or a due to a cardiac effect on the circulation, but unfortunately, the bascular hypothesis of dementia is not exclusionary because you can have toxic insults that affect the mitochondria that will, for all physiological purposes, will do something similar to this cardiovascular insults. In other words, they're going to lead also to down

regulation of cytokromoxidase and your inability to use oxygen to generate energy. So that's why I have used that entry point into the system because it is completely consistent with the vascular hypothesis of dementia, but it also provides room for other insults, the brain that are going to be reflected at that level and is only when they're reflected at the level that then they, because this energetic demand, this vulnerability that you alluded to, that then this is going to lead to a cognitive, why a cognitive problem and not something else? Because when we are engaged in these functions that I explain, these functions are not limited to one region of the brain. They are relied on interaction between different regions.

So when you're reading something, that information goes to your visual system, but then if you're going to engage engage learning having to do with that then we'll engage all the systems so the memory functions are more distributed So when you have a more distributed metabolic insult, they're gonna be affected It's just like people know somebody may get a blow to the head and Then all the sudden they may have retrograde amnesia they may not remember what happened they may remember who they are and you may not see any significant level of structural or functional damage but

you affected the way the systems were interacted in a more global way so this is one of the reasons we detect this tremalia as a memory problem initially, but later on it becomes a narrow degenerative disorder when cells can no longer work without this mitochondrial machinery. Do we have any insight into how much mitophagy or itophagy atophagy is going on in the later stages of Alzheimer's disease. In other words, is it possible that so much of this damage is now due to defective cleaning up of the mitochondria? Because the more these mitochondria are damaged, the more mitochondrial DNA is getting released. The mitochondrial DNA itself is actually, looks bacterial, so it elicits an immune response.

This probably accelerates the process. It would seem that anything that would increase mitophagy or autophagy would at least be able to curb the progression of the feed-forward loop on this damage going and accelerating. Wouldn't that make sense? I agree, however, it's too late. If you already compromise the maturity for obtaining the energy, it's too late at that point. So my focus on the focus of Jack DeLatorian, other people is how can we intervene, for example, one way is in the risk factors. They have to do with the cardiovascular compromise, try to intervene with the risk factors.

Besides blood pressure, what do you view as the most important risk factors then? I think atarosclerosis is a really important risk factor. The major blood vessels you indicated like the carotid, the ascending aorta, and the erenolores. They are the large blood vessels are the main targets of these arterial clotting processes, especially at the bifurcation points. The older factors that I would consider will be generalized trauma to the brain. Yeah, I was going to ask you about this. This seems to bear an uncanny resemblance to chronic traumatic encephalopathy, where the

difference is, if you're a football player or a boxer, you have repeated shortbouts of hypoxia. It appears from my reading of the literature that every time you're getting hit in the head, you're having a transient interruption of blood flow. And also, it appears based on at least the animal models. We're seeing transient insulin resistance at the level of pyruvate dehydrogenase. So a blow to the head will transiently make it harder for pyruvate to turn into acetylCoA, which is the opening substrate in the crebs cycle.

The crebs cycle. The CREB cycle. And so while the patients we're describing who presumably let's just make math simple and say they never get a concussion or a head in the head, they have this chronic and city-us disease process. The athletes who are suffering this type of injury are getting punctuated by spike functions of these, and it doesn't have to be a concussion every time. It could be each play on the the shoulders and like that. Do you think there's an overlap in these processes?

Completely. This is what's called the mancha, pugilistica originally. And often nowadays, this is confused with Alzheimer's disease and Parkinson's disease. In the case of Parkinson's, because when we deblow to the head, there is a rapid twisting of the head. When you get a blow to the head, a rapid twisting bending of the head, we respect to the neck. And that's an angular momentum that usually causes that injury. And these effects, the midbrain and the upper brain is the hem, and actually that's what leads to the knockout. That would feed more into a Parkinsonian phenotype in the midbrain and you'd be...

You would be... Isolating that region is more vulnerable for this, but it is the same phenomena. All of these forms of dementia will have a common denominator at some point, regardless of the many different ways that you can impact the system, the most likely come on the nominated with the level of the mitochondrial respiration. And therefore, another way, for example, the circulation may not be a good target for neurodrioma, but if you find a way to facilitate mitochondrial respiration, even if there is compromise, hyperrefusion, or some other condition.

And this is what I've been working on for many years. And once we discovered that the main problem in the Alzheimer's brain had to do with this inhibition of cytokromoxidase, we set out to, how can we intervene? Is there any way? And you have two interventions that you have now coupled that both work on cytochrome C, but in a slightly different way. Yes, cytochrome C oxidase. Cytochrome C is the carrier and cytochrome C oxidase is the large.

Did large complex, yeah, thank you for clarifying. So the first one, I use a pharmacological approach because I was more familiar with those approaches, but I couldn't do it with regular. Most of what is called neuro pharmacology or psycho pharmacology is really aimed at neurotransmission, receptors and agonies and antagonies. What's needed here is something that's acting at the level of mitochondria and antagonists, what need to hear something is acting at the level of mitochondria respiration and prebuing all literature from the 1960s, I found out that Medellin Blue, commonly used compounds in the lab, was able to act as an electron donor. And depending on the conditions,

but if you make it in a very low concentration, it acts as an electron cyclor. It will donate, but it will also get electrons from other compounds, and it will continue to feed into the electron transport as an alternate route. And in fact, if you block, for example, complex one, we've written on that you're interested, still the electron transport can proceed going through metiline blue as a bypass. Because in a normal organism, complete blocking of complex one would be fatal. You're saying with a high enough concentration of metiline blue, you can still get electrons past the bottleneck of complex one.

We can prevent in animal models, the generation. We chown this in many preparations. We first did it in the retina because it was more accessible. We could manipulate that locally as a model of the brain and then we did it in the brain. So, this has an interesting history, right? There's a guy named Paul Erlich who studied this, right? The only reason I remember this is why do I hear those? Really, yeah. Well, I remed something that I love where expressions come from and so there's an

expression, balls to the wall, which means like going very, very fast all out and most people don't realize, but it just refers to a governor in a train where the governor, the faster that the train was going, these balls that were hanging on, you know, basically cables would move further and further out as the centrifugal force goes. And once they touched the wall, that's the mechanism that would regulate the speed and slow it down. But there's another expression that comes from Erlich's work, which is, is it a magic bullet? Magic bullet. And he referred to Medellin Blu as magic bullet and early Paul early he worked on the Berlin Berlin Germany and he was able to Be part of a very progressive group at the time and Before World War two this was yeah, this is actually this in the late 1800s

No, this isn't a late 1800s 1886 He was working on this and he injected and that time was the beginning of the industrial revolution and the first thing in the industrial revolution that was developed were the text styles, being able to manufacture clothing. And one of the important things was the transition from using natural products for dyes to develop chemists, developing synthetic dyes and actually Germany led this process and Metiland Blue was one of these synthetic dyes, a blue dye, and for many decades it was the blue dye used in blue jeans and most of the other blue clothing. So one of the things

that intrigued Paul Erlich was that he injected Metilin Blue, one of these new synthetic dyes, into a live rat. And then he dissected the animal after killing the animal, he dissected the animal. And he found out that the Metilin Blue, this was a large concentration, intravenous injection, was primarily staining nervous issue, the brain and peripheral nervous issue. So he created the concept there of a magic bullet. This is a chemical that, remember this in the 1880s, this is a chemical that I'm giving systemically, yet it is somehow finding his way to the nervous system and it's becoming trapped there as you can see by the stain. Later this phenomenon was called Superbital or

Vital Staining and it was exploited for example by Santiago Ramónica, one of my other heroes during this time. He referred to this as the early reaction, to be able to stay in nervous tissue when the animal was alive. But what does it mean? The animal being alive, the animal respiring, the animal using oxygen. So metiline blue, they didn't know this, but metiline blue has affinity for these redox reactions that are happening in a maximized way inside the mitochondrial in the electron transport chain. And especially at low concentrations, it becomes trapped for periods of hours inside mitochondrial. It can work as a mitochondrial stain. Does it become toxic at a high, what does it talk to you, yes. At a higher dose, instead of acting as an electron cyclor, it actually replaces oxygen in

the, you know, it competes with oxygen. You remember that I told you oxygen was the one that was taking the electrons. So he can be, you wanted to have it in a low concentration that is giving electrons and taking electrons at the same rate. But you're saying at a higher dose it becomes a proton acceptor. Little. Yes, because it competes with oxygen and it oxidizes the tissues. And actually that was in part the first application that early found for medialin blue. So that's interesting because the only time obviously that I've ever seen it used is

for treating methemoglobinemia in the emergency room. So someone is exposed to carbon monoxide, you know, acutely or even chronically over long and a period of time. This basically breaks it apart. So there you actually want it to sort of outcompete oxygen a little bit, right? Is that what's happening? Yes. Yes.

You know, what is happening there in the car monoxide occupies the in the Hayne molecule, the pocket, were normally oxygen. That's so you actually wanted a competitor. Yeah. You wanted to get the carbon monoxide out. That will displace it. And metiline blue will do that. But because you do this infusion, so metiline blue

can be used to prevent or rescue you from methymoglobinemia, this inability to bind the oxygen, but a higher concentration induces methymoglobinemia. Yes. The same compound. So this is typical of all of these three docs, chemicals that I studied. They have these. They have bimodal functional points. We call this bifasic dose response or a hormetic dose response. Essentially, they do the opposite effects, low and high concentrations. Now the color, if someone's listening to this, I'll remember the high school chemistry class.

How do you demonstrate this to your students? Yes. Well, when you add the powder of metal and blue into water, the water becomes very blue. And then if you use a reducing agent and I use vitamin C as corbic acid, because it's agent and I use vitamin C as corbic acid because it's effective reducing aging but it's harmless. When the metiline blue is reduced, it becomes transparent. Reducing meaning it's accepting protons. Yes, it's no longer acting as oxygen. So then you'll turn that vial clear. Clear. And this is then you'll refer to it as leucco, metiline blue, leuco actually comes on the same root like leuco size, the white blood cells. So you call it the leuco metiline blue that refers to the metiline blue being in the reduced state, as opposed to the oxidized state that is the blue.

So metiline blue had major bandages but one of the cosmetic disadvantages is that once he goes through this process that I explained that becoming trapped, that was discovered by Ehrlichia, becoming trapped in the nervous issue, so he has affinity for nervous issue. Inside mitochondria eventually it goes back into the circulation, it takes half life of about 12 hours with a dose that is a low dose that produces this pre-docs benefit. So it concentrates in the urine in the bladder and actually here in the US for decades before the antibiotics were available. If you had a uninary bladder infection you took metiline blue pills. The metiline blue pills were increasing the concentration of metiline blue inside the bladder until it became a prooxytin while it was there.

And it eliminated any bacteria or virus in a non-specific manner. And it was a very effective, more effective way to eliminate uninary bladder infection, for example, in older people, they have chronic problems that they go through round after round of antibiotics that they validate them or create resistance, you could use metiline blue. And is it because the methanol blue would add a dose that was not toxic to the human? Once it concentrates in the bladder, it increases its concentration and was not toxic to the human, once it concentrates in the bladder, it increases its concentration and therefore is toxic to the organism.

It will become oxidative and it will be toxic for the bacteria. So is it a Ross-induced injury to the bacteria then? Correct. So you're basically going after the mitochondria of the bacteria. Yes, yes, it does the opposite, but it does it to the microorganisms

that are inside the bladder bladder that are producing the infection So it has the potential to do this in all the situation, but here naturally concentrate is there so that provides the advantage But there many things about metyl and bluehood I would not go into but Airlead itself determining that the parasite that produces malaria, the plasmodium falsiparum, had an enzyme that was particularly vulnerable to not much large concentrations of metiline blue were enough to affect this enzyme. So metiline blue became the first and for a long time, the only treatment for malaria. And this was a major breakthrough in medical research, was in fact the first synthetic chemical

used for a medicinal application in the history of medicine and pharmacology, was Medisynal Blue. And all of the first synthetic medicines were derivatives of metilen blue, including in particular the late 1940s, early 1950s, the development of chlorpromising, the first psychopharmacological agent that was used for psychosis or what we call schizophrenia. In those days they will call it dementia precast because they were thinking that it was the same kind of dementia that was happening. The other people happening in the young people, now we make a separation between dementia and schizophrenia. But, cruel promising is a metiline blue derivative and in fact there are reports as far as 19

thudis of physicians giving metiline blue mixes. The problem was that in the original way that medialin blue was synthesized for textiles, there were a lot of intermediary products as a result of the synthesis and some of these were likely chlorpromising. So they were seeing anti-saggotic effects from giving these metiline blue preparations, as I found reports in the 1930s and 1940s, and then they was picked up by pharmaceutical company, and by the end of the 1940s, they developed chlorpromising as the first anti-psychotic medication, and that would change completely the face of psychiatric. And it may have just been simply a chemical contaminant slash intermediary contaminant

within the formulation of the same disease. So they thought the benefit was metering blue. It was actually from a byproduct within. And they'd just go or what the byproduct was. Which is such a great story of chemistry in general, right? So easy it is to be fooled by something that, you know, seemingly makes sense. Now today, the only FDA indication to my knowledge for methylene blue is is methemic lobotomymias.

Correct. Yes. I mean, there's clinical trials that are going on to study this in law's largest disease. Yeah. Let me clarify that because what happened is that methylene blue was being available for 120 years plus. So, Metilin Blue was grandfathered by the FDA. It preceded the creation of the FDA. So, the FDA has not been able to resolve, well, how they deal with these grandfathered drugs. Being the first synthetic drug available, so it was used

for many things. I'm not going to go into all of them but malaria was probably the most important one until some Spanish and French explorers in South America discovered from the part of the tree, Queenine, and then that happened and it became the next generation after Medellin blue, now they are bringing back the metiland blue especially in Africa because they are the plusmodium has come persistent to winines, so they are combining it, so there is a comeback for metiland blue in that respect. So it is used medicinal for that, but the FDA never really got to have a saying on it. So what you're referring to is what has survived in the what is called the US pharmacopea. These companions of medications with indications. And in the US pharmacopea, that indication of metiline blue for metimoglobinemia has survived. Some of the others have been removed, like I told you, for uninary bladder infections when

the antibiotics became available. But it's being used to protect the brain. You mention cancer early before we started the interview. Many of the drugs that are used for chemotherapy have side effects that affect the brain, in particular mitocondrial respiration. So, metaline blue, given before or during chemotherapy interventions, are being found to be life-saving. One example is one called eye phosphamide. So, eye phosphamide, induced and cephalopathy happens in this chemotherapy, and there are many papers on these. However,

the problem is the FDA will not acknowledge these uses because there is no pharmaceutical company who is bringing these materials. I guess this is sort of an impossible situation to understand because the FDA can't really consider the approval for an agent or a use without an investigational new drug filing an IND. There's no IND, I assume, for methulin blue because there's no economics in methulin blue. Yeah, there is no company that wants to invest because it's not patentable. They cannot protect their with a patent. So anybody can manufacture metiline blue and prescribe it or use it.

In some countries like Canada, it's freely available. Here in the US, it's unclear what is a status is, but you can get it through the internet. The problem is there are two problems. One, you have different purities. So you have at least three categories of purities for metilen blue. The one that should be used by in humans like in the emergency room is the so-called pharmaceutical quality or the US.

We call USP grade. The Europeans have a similar, but the one in the, the USP is actually more restrained than the European medialemblu. Then there is chemical quality that is used in laboratory for staining, but that can go for, for example, the one produced by Sigma has about 15% impurities. It should not be given to live animals or humans, and is readily available. So I always want to warn against that. And in many experiments with animals, they use that sigma-prolo. So we don't know if we're confounding the results of the experiments with the impurities.

And impurities are very toxic. He has lead, he has mercury, he has cadmium, he has a number of neurotoxic impurities. And then the other one is even less pure, is the industrial color of the genes, to color the blue genes and all the things, and that is even more than 15% impurity and nobody knows, which you're. Now, there was a company in Scotland several years ago

that ran a compound LMTM, and the trial, which was announced, results of this trial were announced about two years ago, and it was a big hoopla because the study, which I went back and skimmed the other day because I knew we would probably, I was hoping we would talk about this. The study basically took patients in early stages of dementia, randomized them to various interventions, but one of them was this agent, this LMTM, which they describe as a methylene blue derivative.

I don't know how far a derivative it was. It might have been not much of a derivative. It's essentially, you remember when I told you, I added a scorvic acid, to reduce methylene blue, so they don't something like this. They have reduced methylene blue, but they don't use the name

metiline blue. They use the name of a metil-tioninion chloride, which is a more chemical name. And that's where the empty comes. And then the L is for the leucle. Because it's clear it comes in its reduced form. That's the form that is in the peel. As soon as it's in the body, it's oxidative. Yeah, it starts these redolk cycles. And those patients did void blue. Oh yes. So it is clear that it's doing the redolk cycles. Now what was very controversial about this was the primary endpoint of that study was a neuroimaging outcome.

And the primary output failed. There was no difference on neuroimaging outcome and the primary output failed. There was no difference on neuroimaging. There was a secondary outcome on cognitive function and in a subgroup analysis, which again, the statisticians will say that's, you they cry foul, right? And understandable. You can't start parsing the data. On I agree. Yes.

But the argument was The subset in which this benefit was seen which was about 15% and if I recall it was only patients that received the LMT I'm in monotherapy So what we don't know unfortunately because this to me left a lot of questions unanswered, right? It certainly suggested there's something going on with methylene blue But are we being misled because the combination of methylene blue with other drugs obfuscates the results? Yes. I think that's the most likely.

That's one. Yeah. No, it is the most likely. Oh, yes. However, let me clarify. This individuals have never presented methylene blue or understood methylene blue from the point of view that are being presented to you as a metabolic enhancer or it could be Metabolic poison too, but in low concentration

The low concentrations as a metabolic enhancer acting on the mitochondria respiration They are having presented these as an anti-tow Medication that's correct. The entire company, what whose name I forget now, yes, go towel. It had towel in the name, yes, X. Yeah, yeah. That's the other thing that interested me, which was,

hypothesis is completely wrong. They might have backed into something interesting, potentially. Yes, and I say this here publicly. It is unfortunate that they have done this this way because they are undermining the potential benefits of metilen blue. The biochemist who is behind the hypothesis are not going to name. He found that in vitro, relatively large concentrations to relatively large concentrations to basing what I'm telling you about mitochondrial respiration. It prevented the phosphorylation and agglutination of tau in vitro. So they infer or this is an anti-tau agent.

If you test metiline blue with a mediate different compounds, depending on the concentration of metiline blue, because it has reducing or an oxidating action, it will interfere with all kinds of phenomena. There is nothing specific about metiline blue. This may be true, true and unrelated. It's effect on tau, whether correct or incorrect, may not actually matter. And not only that, the effect is those dependent, in other words, in B-throw, the more concentration, Medellin Blue had you, the more you interfere with the tau aggregation. In other words, you don't see this bimodal dose response.

No, because they were actually working on the high end of concentration. So does that mean they weren't even looking to see what the toxicity was in the mitochondria when they did the initial work? They did some later work that to address this when they wanted to move this to the FDA. But the point is, in the first studies from this group, the most effective dose was the lowest dose. And it was in the monotherapy group. Yes, this was before that study. group. Yes, this was not.

This was before that study. Before that study that you're citing. Oh, this is the phase two. That was the first one. That was the first one. In the first study, they found some effect with the very low dose. And in the higher doses that would approximate

this anti-tow effects, they found no effects. And they turned this around in such a way that in one of the papers published in the journal Alzheimer's disease that friend of mine is the editor, they claimed that actually the highest dose there was a problem with that solution and it was really a low dose and the load Lowest dose was more easily absorbed and it was really then the high dose and then they Strange the result to indicate all the low dose was the high and the high dose was the low and that's why it worked So in other words, they did not change their hypotheses that was contradicted by their data, which is the same thing that's been happening with the Ameloid

people, their results, they're not supporting their hypotheses and they keep blindly moving forward. So now what you were explaining was because they have difficulties getting a patent for this compound. They created this reduced version of Medellin Blue and did similar studies, but in that study they had the problem that the majority of the people, if you are having Alzheimer's disease and you're in a hospital or being treated by usually neurologists, sometimes I get this, they would prescribe, unfortunately, unfortunately, drugs that have not benefit through the patients, but produce a verse of X such as colonester as inhibitors and mementine.

And the idea being as well, this is the standard of care. It would be quote unquote unethical to take these patients off these agents, even to allow them to enter another trial. Well, that may be the reasoning that some people may have, but that's actually the opposite of what's happening. These drugs are ineffective and is unethical to continue to use these ineffective dose that are having these toxic and adverse effects on people. If you go back to the original studies that were used by the FDA to approve these drugs,

and the reviews that were done subsequently by the Crochane Groups Metanalysis, they all conclude very clearly that these drugs are ineffective and they do not improve activities of daily living and that the disease continues and progress and people die. In fact, in countries where they have more elaborate longitudinal data like in the UK of administration of these compounds to patients with Alzheimer's, they know that they die sooner if they're taking these medications that the ones are refused to take them. And the UK made an attempt. In fact, they banned these compounds because they had evidence-based. They're not only they were ineffective, but they were counterproductive. And within a year, the public demanded to the politicians because

if they're used in the US, they must be beneficial. And so this is a decision that was on politically motivated to bring them back and make them available, even though we have all the evidence, just like we have against the amylo hypothesis that the cholinergic hypothesis of Alzheimer's disease is also irrelevant. I actually, it's funny, I didn't realize people still subscribe to that hypothesis. The most commonly prescribed medications are the cholinesterous inhibitors. And then the FDA did not approve,ementin for early Alzheimer's or mild Alzheimer's or myocondyl impairment. They approved originally only for severe and then later for moderate and severe which was

very unfortunate. The Mementin is preventing some of the excitotoxicity that is damaging those hyocampal cells, but essentially what you're doing when you do that, you are rescuing from dying a cell that is functionally incompetent. Yeah, so indirectly, which is interesting, because there was a study that came out about a month and a half ago on Mementin, and I remember, you know, this is obviously not my field of expertise,

so my level of knowledge in the literature is so much less than other areas. But the problem with that could be that you are actually rescuing a cell that's gonna go on to send a signal that could cause more damage down the line. It is completely counter-prolonged. And it's based on the pathology, pathology oriented

that you can see more of these neurons there when the people die. But it's not a functional assay. In other words, it's a neuropathological, which there's value in these things, but it sounds like the real overarching challenge here is triangulating between neurobiology, anatomy, functional signaling, and then, of course, ultimately, clinical outcomes matter more than any of these other things in the end. I agree.

And that's what should direct all of this in the first place and it's now what's happening. Now, I know this is a little outside of the work you do, but do you have a point of view on the recent excitement around Purpose Simplex virus one? Have you followed that discussion? No, I don't have a good point of view. What I can tell you is we found another way to try to intervene with mitochondrial respiration using light, in particular infrared light that can go through the tissues and the photons in the near infrared light are absorbed by cytokromoxidates. It turns out that cytokromoxidates, that's the name cytocell, but chrom color is because of its

axor, certain wavelengths, and it reflects all their soils, the chemical in the cell that gives color to the cell. And this property of photonic axor, we have used in conjunction with the laser delivery of near infrared light, transgranally through the forehead has a source of photons that actually oxidizes photo oxidizes cytochrome oxidase. And by doing that, the M sign has more affinity. That's the confirmation of the M sign that has more affinity to oxygen for oxygen consumption. Yeah, I just pulled out a picture that will make sure we link to in the show notes that comes from one of your papers actually, where it shows in the same figure, a close section of the

mitochondria, and you can see the effective methylene blue, and also the effective near infrared light. Now, it strikes me as interesting that you can get the wavelength just right because you have to be able to get through not just the tissue, but the skull itself. Actually, this goal is less of a problem. It's easier to grow. Because it's porous, because of the bony matrix, or... Yeah, because there is less circulation through it. One of the big bromo force that we have is hemoglobin. I see, so hemoglobin can absorb and reflect much of the slide before it actually reaches the neuron.

So what we try to do is we move away from this peak of exhaustion, so oxy and the oxy hemoglobin to one that is still can be absorbed by cytochrome oxidase. To how many nanometers then? We use 1064 nanometers wavelength, so around 1000, which is a wavelength that is not very well studied in biochemistry. Most of the spectrophotometers in biochemistry, they do not go all the way to one thousand. Yeah, they're in the hundreds, usually. Yes, they usually end up.

300 to 800 or something. Yes. But the longer the wavelength, the more it penetrates to the tissues. How do we know how safe that is? I'm sure somebody listening to this is going to say, wait, that sounds like microwaving my brain, like, how? No, of course, it's a different wavelength, no, I understand. But as the sort of lay person, this sounds very scary, right?

Microways moving the other reaction, but the longer the wavelength, the less energy they carry. So the less they can penetrate, so they cannot really penetrate inside atoms, like the ones that have chore wavelengths, but they are good enough to penetrate to the tissues, not very deep, and only about 1 to 2 percent if we do it transgranally through the head, actually goes through to the surface of the cerebral cortex. Once in the cerebral cortex the Y-matter is also a barrier so the effect of the photons is primarily in the great matter layer of the cerebral cortex.

And what it does is it is it is donating these photons to the electron transport. So you're bypassing the electron donors. By the photons are not identical to electrons, but they act in a similar way in the electron transport. So the photons and the electrons are very similar. The difference is that the electron can carry a very small mass. Photon essentially do not have mass. And by providing photons to the electron transport, you keep the electron transport going because these enzymes engage in the

redox changes. And the more photons you send to cytokromoxid, the more of the enzyme quickly goes to the oxidized confirmation. And the oxidized confirmation is the one that has more affinity to bind oxygen. But I don't understand how is this actually making its way systemically to the brain through a transcranial stimulation. When you aim through, for example, the forehead, it goes through the tissue and reaches the surface of the cerebral cortex. And that's how it makes its way. It's a more localized, it's different from, it's not a systemic administration like Medellin Blue. And is it enough to just be able to hit the frontal cortex

to create a clinical improvement without impacting the mitochondrial function deeper in the midbrain or lower part of the cortex. To create a functional improvement, we don't know yet about clinical, especially I would not say that in somebody with the degree of atrophy that many of their Alzheimer's patients have, we're going to have enough substrate there to be able to stimulate and reverse the disease. So this will have to be tested with clinical population. Are there clinical trials that are going to be looking at this near infrared light?

Yes. Strategy combined with methylene blue? Nope, not combined. You don't think of these as synergistic. You consider these separate approaches? Yeah, I consider them separate approaches. The reason for this is the following. Medellin blue can affect these photons. Of course, that makes sense. And this is actually used nowadays. For example, their metologies. If you have a melanoma, a cancer in your skin or any other lesion, they can inject metiline blue into that region. And then they just shine light.

And they light. Concentrates the light. Into metiline blue and the metiline blue oxidizes the act. You have that raw reaction in the same thing that you see in the bladder. And it kills those cells there. This is called photodynamic therapy. You have that roster reaction, the same thing that you see in the bladder. And it kills those cells there. This is called photodynamic therapy. It has many applications because if you have a virus that you have no way to kill, you

can always kill it this way. So this is happening. Even people don't know, metalym blue is injected into blood that is used for transfusion, so that you can then treat this blood with this bright light and by photodynamic therapy kill viruses like the HIV virus or the herpes. Is there a difference between giving the methylene blue orally versus intravenously? Yes, specifically. Yes, the intravenous one one the first target will be the blood cells So you have to be more careful with the concentration because you don't want to

Promote the met him or Grubinia in other words to compete with oxygen. Yeah, so it seems safer to administer oral Yes, the oral administration produces slower release and in low concentration is very safe and And it's like I say, it's being done in thousands and thousands of people for malaria. And it's studies that have been published in the last few years, have primarily given to children in Africa for killing the parasites. And in that case, the oral administration has the advantage that many of these parasites are... In the gut as well. Yeah, in the gut, so you ministry has the advantage that many of these parasites are in the gut as well. Yeah, in the gut soil, you can have the higher amounts there.

So going back to this broader perspective, and the clear theme here is, which I think is that prevention matters. In fact, we shouldn't be focusing so many resources on the treatment of clinically evident apparent dementia for the reasons you've discussed. So now what we want to do is prevent. I was going to say prevent in high-risk individuals, but as one of my friends who's a neurologist would say anybody with a brain is at risk. So let's stop stratifying as whose high risk versus low risk. Everybody should take a preventative measure. Yes, definitely.

In addition to this idea of all the things that matter in the heart, so lower smoking, lower blood pressure, better glycemic control, better management of lipoproteins, etc., etc. Is there anything that you see as unique in the brain specifically that is maybe not unique or maybe not as important in the prevention of cardiovascular disease? The only one that I would say will have to do with the ketogenic diet. Ketogenic diet will facilitate mitochondrial respiration in a different way, but this will contribute to targeting mitochondrial respiration.

So that the brain will benefit more than they are. The heart will benefit, of course, all of these tissues will benefit, but because of the brain reliance on hydraulic metabolism. For example, you alluded, for example, at insulin resistance. One of the problems that happens as the brain ages, even in normal people, is that the transport of glucose is affected. So even though we can increase glucose levels in the blood or what we eating, we cannot get that glucose being transported to the brain as effectively as in the younger individuals. That's why some of these studies with intranasal insulin administration show transient improvement in symptoms presumably because they're becoming resistant. Because now that's obviously not a long-term solution.

No, but it illustrates a point. And fortunately, insulin primarily facilitates glucose transports in all the tissues, all the time the brain. The brain actually doesn't require insulin. It can boost its transport of glucose. But the reason for that is that when you wake up in the morning that you have been fasting overnight, whatever levels of glucose are circulating in your blood, then the brain tissue will be the only one that will be able to take that

up. And it's only when you have large glucose levels that the insulin is released by the pancreas and then all the tissues they can use, they can feast on it. So the ketogenic diet, so ketombolis can act as an alternative source for energy in the brain. And the important point is that even though glucose is a preferred substrate during aging, this is compromised, this uptake. However, the uptake of keton bodies is not compromised. Therefore, you could satisfy some of these regional requirements by adding the keton bodies to the diet. Do you think it matters if a person is on a ketogenic diet or if

they're on a non ketogenic diet, but they supplement with exogenous ketones? I hope it doesn't matter. Has long as you have the ketone bodies available, you don't require to have the ketogenic diet itself, but this eventually will have to be resolved empirically. And there is no question that is going to promote mitochondrial respiration. And we know, as you know, when we're born, as infants, we rely primarily for neural function and everything else on this ketone bodies, produced by the liver, but because of the kind of lipids that we get through the mother's milk. So essentially, what we're trying to do is bring in somebody who is in all age to rely more on ketosis, that is a process that we know exists on the physiological conditions

every day. If we go beyond 12, 14 hours without eating, we start generating this. But it's all in saying that we know in infancy is the primary source for the brain. I didn't realize that. Is that more a result of their liver is not being able to release enough glycogen via glucose and empathic glucose output? I mean, I know they have a very high demand for energy. Can you measure the ketone in their blood?

Yes. But it is because of the source of food that they are thinking. I see. So they're basically getting medium chain triglycerides through the milk. Yes. The medium chain triglycerides being the main source there for energy conversion as opposed to some of the other triglycerides. So the original bulletproof coffee is actually mother's breast milk before it is the fancy coffee is that everybody drinks. Yes. So I do believe that that's another alternative. So in essence, you could potentially have pharmacological interventions that address mitochondria respiration, but they will not have to be classic pharmacology, like neurotransmitter-based pharmacology.

There will be more of a metabolic pharmacology. You can have near infrared light by providing this photonic stimulation. However, that one is targeted, it's not systemic like you pointed out. So one will have to find target locally. The forehead is more accessible, we don't have hairs. And we can target that prefrontal cortex

that shows the initial cognitive difficulties as people become older. And that's what we have been doing. And then the third one will be through the diet, which you facilitate, because as you pointed out, the insulin resistance is because our glucose levels are going up because we cannot transported it into the tissues, especially nervous tissue, which was a primary consumer, has effectively, and then we have these high levels of glucose for longer times. So there's more insulin that is being released and then this sensitizes the receptors.

So there is a natural development of metabolic syndrome as we grow all because of this phenomenon. This manifests itself then has less substrate for energy for the brain and then you have a kind of decline accelerated associated with obesity and hypertension and this insulin resistance. So it's all part of the same age-related picture. And probably people eat more because they are trying to make up for this lack of energy that the brain is consuming. And if any organ is more liable to influence our eating behavior, it will be the neural tissue.

That's such an interesting thought because I've always believed as you've suggested that I think our appetite is driven by fundamentally important physiologic processes and starvation would be the most important among them. And starvation in the modern world doesn't look like starvation in the prehistoric world. Starvation in the modern world can be in the presence of obesity because because we're not talking about the obvious, we're talking about the cellular level. And so if cellular metabolism is deficient, which is often the case in insulin resistance, an individual can be functionally starving, and that can drive it. Now, I've always thought about it through the lens of the liver, but you're making an

argument that says there's also a central starvation and it could be also driving these repetitive changes. But they're all also peripheral components, like you say. For example, the case of the obese, an individual that has obesity will, by almost definition, will have down-regulated the keto-genesis. The keto-genesis M-sign will not be up-regulated the ketogenesis. The ketogenesis, M-sign, will not be up-regulated unless you're consuming your own fat. And these are trainable M-sign, like indusual as well. So if you don't go through periods of fasting, you cannot elevate this M-sign.

So somebody who is obese and suddenly stops eating is starved because his body cannot. It doesn't happen. Yeah, and the presence of hyperinsulinemia, it is a very painful transition into fasting. You cannot use your body fat to feed, especially the brain, which is the first one that is going to give you these signs and symptoms. So the first thing that somebody has to do is start out by having a periodic video, so fasting that in my own case, I do it once a week, usually between Friday and Saturday, I fast for at least 14 or 16 hours, you know, it's not difficult to do if you have an early meal and then a late brunch, you will have significant fasting and you can accelerate that

process by consuming some of the circulating glucose if you do a workout that morning. So by doing that, I am allowing my body to build up these ketogenic enzymes. And therefore, then during a regular day in the week, if I don't eat anything between meals, I don't feel hungry because I can consume my own body fat. And people who are obese cannot do that. They don't have the biochemical machinery to do it. So I believe that's probably the third way of approaching this problem,

if those three things could be used. And like I say, it may not be possible to combine some of them. I will have to empirical determine how much metal and blue one can have systemically so that to not produce a photo dynamic effect when I do transgranular laser stimulation. We hope in the future we may be able to do this with LEDs. Right now with the LEDs are commercially available, we haven't been able to find the results

that we get, but we are investing time in trying to change this, so it would be safer and cheaper to do. So right now, the only ones. So my bioengineering colleagues has been able to collaborate with me and develop a device that we can transgranally do imaging with near-infrared spectroscopy and actually measure the concentrations of oxidized cytogram oxidized in people in the human brain. And we published that last year and this allows to directly have a measurement that we are indeed engaging our target. And this also allows to find what is the optimal dose response

for that particular brain. Because like you indicated different people at different heads and the transmission would not be equivalent. So this is what we're doing. And so we have obtained three major grants for doing this with the bioengineering group in the Dallas area. For example, Professor Henley Liu, we are doing the development of these devices to monitor the physiological changes. And this is a grant by any age that is called the Brain Initiative Program. And then here with my colleague, Adriana Halley, we have a grant from the natural institute of aging to test this transgranial neodym篤-er-light in older people and people with mild cognitive impairment. And then the third has been a benefactor who's giving us large amounts of

money so that we can pursue these line of work with the transgranial lasers. And I can show you the endorsement from some of the people in the field. Oh, yeah, I'll take a picture of this and we'll put this on. In fact, it was actually Jack who directed me, too, speak with you maybe six months ago. This is exciting.

I want to add one other thought to this, which is I hope that if somebody's listening to this who's involved in traumatic brain injury, that someone ought to look into a clinical trial of using methylene blue as a rescue agent during periods of traumatic injury. Because again, mechanistically, it's at least plausible that you could salvage and rescue some of the transient insult and the damage that goes through that. And again, there's another example of a disease

for which we don't seem to have any solution other than the obvious, which is avoidance of the injury, the insult. But there's still a lot of people out there that are being exposed to repetitive head trauma. And, you know, as you probably know, there's been some interesting hypotheses around the presence of ketones in the system

before traumatic injury and potentially a salvage after, but it seems to me that this methylene blue story probably deserves a bit more attention in other areas given these properties you've described. I actually agree with you and I would say because it's using emergency rooms, I believe, in every ambulance, you should have metiline blue available. And if there is any insult that compromises metabolic supply to the brain, you're going to be better off infusing metiline blue at a low concentration. We're talking about one milligram per kilogram concentration.

That is going to be neuroprotective. Regardless of the source of the, it could be transiting a chemical track, it could be an stroke. We have done this in a stroke models in animals using the methyl and blue. And we can be able to rescue the majority of the damage produced in the infarge, in animal models, when we look at this longitudinal using FMRI. So we know this working animal. I just been unable to convince emergency physicians to start doing this to their scamic patients and not only for the brain but scamia affecting all the other organs.

It is also being tried in animal models of Netrauma with the similar benefits. So the problem is there is no interest by the pharmaceutical company because they can make money on it. And unfortunately, the NEAH is also influenced by if you're using an old drug, essentially, you're repositioning this old drug for these other applications of some neuroprotective engine or more generally metabolic protective engine. They are concerned that their investment is not going to panel out because when it goes to commercialization, you're not going to be able to patent that medication and believe it or not, even though it works, if there is no prospect that profits can be made.

They don't want to invest. Yeah, it's a shame because I worry that we'll be in the state of limbo where we're not really going to know the answer. And we can't know the answer without clinical trials. This is about as easy and agent as there is to study, given its long history, its relatively well understood toxicity profile. And in many cases, the speed with which you could see a response, especially if you're studying ischemic events. And I will tell you that just a couple of years ago, was published last year, the group that

I collaborated with in San Antonio, we were the first to show the effects of metilen blue in the human brain using FMRI and measuring blood flow, measuring bold signals. And also in those subjects we did memory testing and we were able to demonstrate a significant improvement in their memory retrieval just going to acute treatment with medial and blue in a blind placebo control study, the first time that that was done, contrary to these other groups that are doing it as an anti-tow Asian, in healthy and older people, we can improve memory and we can demonstrate using imaging that we can do this through metiline blue. So the only problem is there's not going to be any profit because I believe its own company will like to develop this purity pharmaceutical grade metiline blue. There will be a huge market. All the companies may imitate them, but there is enough for everybody. Still the cosmetic aspect of having you in this scholar is a problem. Many people will not accept it.

Yeah. Well, Francisco, this has been great. You've been very generous with your time. And I really appreciate this discussion. I've learned a lot. And I'm guessing that people listening to this will have also learned a lot. So we will have a great set of show notes to accompany this where all of the papers that we've talked about are linked to Jack's book and a number of other things will be included. So that hopefully it's a reference for anyone else you want to share this with and certainly anyone who wants to. So thank you very much. Thank you, Pete.

You can find all of this information and more at pterotiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at pterotiamd.com. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID, Peter, ATF, MD.

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