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Elevated levels of ketone bodies, such as beta-hydroxybutyrate, can have beneficial effects on several brain-related diseases. Research suggests that ketone bodies can increase blood flow in the brain by 30 to 40 percent, which may have profound effects for patients with brain injury or vascular dementia. By studying ischemic wounds, which are analogous to an aged brain or clogged arteries, researchers observed increased blood flow when ketone levels were elevated. Nutritional ketosis may also reduce neural inflammation which may be a predictor of seizure in epilepsy. In this clip, Dr. Dominic D'Agostino describes the positive effects that ketones can have on the brain.
Dom: You're referring to the Henderson paper where they looked at...
Rhonda: Both papers.
Dom: ...Axona AC-1202? So the finding was in that study, which is relatively small, that at least not with the diet, but using a ketone supplement that was formulated with 20 grams of medium-chain triglycerides. So they gave to their patients, I think, just once a day. And they did show fairly convincingly that the elevation of beta-hydroxybutyrate correlated with an improvement in cognitive function, but that correlation was not observed in the ApoE4 positive group, which was a little bit...it was kind of surprising. I would like to see that study done using the ketogenic diet or maybe the ketogenic diet formulated with ketone supplementation. So, the question is...it did not have a negative effect, but the question is why didn't it have a positive effect?
Rhonda: Was there not another study where they actually did the ketone supplement, beta-hydroxybutyrate? I thought there was, but I could be mistaken just from my lack understanding because that would shed some more light.
Dom: Yeah, well, they used caprylic triglycerides, C8, which kind of makes a lot of ketones, relatively speaking.
Rhonda: Unless the ApoE is changing the way you're making ketones, right?
Dom: With fatty acids, yeah.
Rhonda: But they measured, you said they measured beta-hydroxybutyrate in everyone and the levels were the same because it's like I want to understand why there was no positive benefit in ApoE4 carriers because that's the one thing that...it seems so promising, right, that these ketone, potentially ketone supplements or a ketogenic diet can help modulate Alzheimer's disease.
Dom: Yeah, we...and I think you could do it in different ways. My student presented yesterday, she presented this week, but she graduated with her Ph.D. yesterday and her work showed that there's a remarkable increase in blood flow, and previous work has shown that ketone bodies can increase brain blood flow by 30% to 40%. So that's another, when you have vascular dementia, when you have a decreased, that being, staying in a state of nutritional ketogenesis...
Rhonda: Or just brain injury in general.
Dom: Yeah, it can have a profound effect.
Rhonda: Did she understand any of the mechanisms or do you know? Can you talk about it?
Dom: Yeah, we're looking at that. Well, we did ischemic wounds, which I mean, I guess you could kind of relate to an aged brain, right, with clogged arteries. We did a Doppler blood flow measurement and showed that it spiked up considerably when we can elevate ketones. One of the things, it was not dependent upon VEGF. So we looked at all the different factors, so VEGF was not increased in the wound. We looked at a couple of different other things that we thought would be increased. Well, the one thing that stood out in the data was adenosine. So adenosine levels are significantly elevated. Now adenosine is sort of thought to make us sleepy. You know, when we drink coffee, it's like an adenosine receptor antagonist.
Rhonda: No way.
Dom: There's high levels of ATP, sort of, being used and we think that they may be causing an elevation of adenosine, but we really have to delve into the metabolomics to understand why that's happening. Regardless, adenosine is a very powerful vasodilator, and it's in higher concentrations, significantly, in the blood and that may be increasing the profusion of tissues, peripheral tissues, and I think that was it.
Rhonda: That's great. Did it have any effect on blood-brain barrier at all as you look at that?
Dom: We haven't looked at that. My colleague has been, kind of, looking at that a little bit. We know with fasting and the ketogenic diet that you can increase permeability to the blood-brain barrier. Things get through faster.
Rhonda: You mean ketosis through fasting or both, combining the two?
Dom: Well, yeah, sort of, yeah, fasting-induced ketosis or even the ketogenic diet can help increase the permeability of the blood-brain barrier to a wide variety of things. So if you are, sort of, the implications from his perspective that if you're getting a chemotherapeutic drug, if you're getting some kind of drug that needs to cross the blood-brain barrier that's impaired in some way, you might be able to get that across faster in a state of fasting ketosis or the ketogenic diet.
So maybe if you're fasting maybe there's just less stuff in your blood, there's competition of things getting through and your blood's sort of clear and you introduce the drug and you get more rapid transport because there's co-transporters and other things or things that might be in their diet that may be impeding transport, there's multiple independent lines of evidence to suggest that being in a state of ketosis can help better transport things across, but when we talk about permeabilizing the blood-brain barrier, that's like a bad thing, right, making it more permeable. In general, though, you get a knockdown of neural inflammation from the diet and from therapeutic ketosis, which is something the epilepsy world is very interested in. So there's a PET scan technique that allows us to look at neural inflammation in the brain and we know that...this is a conference that I recently came from, that maybe an excellent predictor of when someone's going to have a seizure.
A purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule. Plays a role in regulating blood flow to various organs as a vasodilator, and, in its role as a neuromodulator, adenosine is believed to promote sleep and suppress arousal. Adenosine is also involved in energy transfer as ATP and ADP, and signal transduction when in the form of cAMP.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
One of three common genetic variants of the APOE (apolipoprotein E) gene. The APOE4 allele, which is present in approximately 10-15% of people, increases the risk of developing Alzheimer's disease and lowers the age of onset. Having one copy of E4 increases risk 2- to 3-fold, while having two copies increases risk as much as 15-fold.
A chemical produced in the liver via the breakdown of fatty acids. Beta-hydroxybutyrate is a type of ketone body. It can be used to produce energy inside the mitochondria and acts as a signaling molecule that alters gene expression by inhibiting a class of enzymes known as histone deacetylases.
A highly selective semi-permeable barrier in the brain made up of endothelial cells connected by tight junctions. The blood-brain barrier separates the circulating blood from the brain's extracellular fluid in the central nervous system. Whereas water, lipid-soluble molecules, and some gases can pass through the blood-brain barrier via passive diffusion, molecules such as glucose and amino acids that are crucial to neural function enter via selective transport. The barrier prevents the entry of lipophilic substances that may be neurotoxic via an active transport mechanism.
A general term referring to cognitive decline that interferes with normal daily living. Dementia commonly occurs in older age and is characterized by progressive loss of memory, executive function, and reasoning. Approximately 70 percent of all dementia cases are due to Alzheimer’s disease.
A molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A metabolic pathway in which organisms produce ketones. Ketogenesis occurs primarily in the mitochondria of liver cells via the breakdown of fatty acids and ketogenic amino acids. Insulin is the major hormonal regulator of ketogenesis; however, glucagon, cortisol, thyroid hormones, and catecholamines can induce greater breakdown of free fatty acids, thereby increasing the substrates available for use in the ketogenic pathway. The primary ketones used by the body for energy are acetoacetate and beta-hydroxybutyrate.
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
A class of saturated fats. Medium-chain triglycerides are composed of medium-length fatty acid chains (six to 12 carbons long) bound by a glycerol backbone. They occur naturally in coconut oil, palm oil, and butter, but they can also be synthesized in a laboratory or food processing setting. Evidence suggests that MCT therapy improves cognitive function in older adults with Alzheimer's disease.[1] Examples of MCTs include caprylic acid (C8), capric acid (C10), and lauric acid (C12).
A type of imaging test that uses a radioactive substance (tracer) to look for disease in the body. For cancer detection/metastasis the tracer used is fluorodeoxyglucose, an analogue of glucose. The concentrations of tracer imaged indicate tissue metabolic activity as it corresponds to regional glucose uptake.
A molecule composed of a glycerol molecule bound to three fatty acids. Triglycerides are the primary component of very-low-density lipoproteins (VLDL). They serve as a source of energy. Triglycerides are metabolized in the intestine, absorbed by intestinal cells, and combined with cholesterol and proteins to form chylomicrons, which are transported in lymph to the bloodstream.
A progressive worsening of memory and other cognitive functions that is thought to be due to chronic reduced blood flow to the brain which is commonly due to the accumulation of cholesterol and other substances in the blood vessel walls that obstruct the flow of blood to the brain.
Originally known as vascular permeability factor (VPF). VEGF's normal function is to create new blood vessels during embryonic development, after injury, in muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply, and cancers that can express VEGF are able to grow and metastasize.
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