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CME

Brain Glucose Hypometabolism, Ketosis, and Alzheimer Disease: From Controversy to Consensus

  • Authors: Richard S. Isaacson, MD; Stephen C. Cunnane, PhD; Russell H. Swerdlow, MD
  • CME Released: 8/27/2013
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 8/27/2014
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Target Audience and Goal Statement

This activity is intended for neurologists, primary care physicians, and other healthcare practitioners involved in the diagnosis and treatment of Alzheimer disease.

The goal of this activity is to educate clinicians about brain glucose hypometabolism and the role of ketosis in preserving cognitive function in patients with Alzheimer disease.

Upon completion of this activity, participants will be able to:

  1. Discuss results of clinical research on brain glucose hypometabolism as a pathologic characteristic of Alzheimer disease
  2. Describe the rationale for treatment to address brain glucose hypometabolism
  3. Compare and contrast strategies to induce ketosis to address brain glucose hypometabolism


Disclosures

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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Authors

  • Richard S. Isaacson, MD

    Associate Professor of Neurology; Director, Alzheimer’s Prevention and Treatment Program, Weill Cornell Medical College, New York, New York

    Disclosures

    Disclosure: Richard S. Isaacson, MD has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Accera, Inc.; Novartis Pharmaceuticals Corporation
    Served as a speaker or a member of a speakers bureau for: Novartis Pharmaceuticals Corporation

    Dr Isaacson does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Isaacson does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Stephen C. Cunnane, PhD

    Professor of Medicine and Physiology, University of Sherbrooke; Former Director, Research Center on Aging, Sherbrooke University Geriatric Institute, Sherbrooke, Quebec, Canada

    Disclosures

    Disclosure: Stephen C. Cunnane, PhD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Accera, Inc.

    Dr Cunnane does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Cunnane does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Russell H. Swerdlow, MD

    Professor of Neurology; Director, University of Kansas Alzheimer Disease Center, Kansas University Medical Center Neurodegenerative Disorders Program, Kansas City, Kansas

    Disclosures

    Disclosure: Russell H. Swerdlow, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Accera, Inc.

    Dr Swerdlow does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Swerdlow does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

Editor

  • Ron Schaumburg, MA

    Scientific Director, Medscape, LLC

    Disclosures

    Disclosure: Ron Schaumburg, MA, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC

    Disclosures

    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed the following relevant financial relationships:
Received grants for clinical research from: Ortho-McNeil-Janssen Pharmaceuticals, Inc.


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CME

Brain Glucose Hypometabolism, Ketosis, and Alzheimer Disease: From Controversy to Consensus

Authors: Richard S. Isaacson, MD; Stephen C. Cunnane, PhD; Russell H. Swerdlow, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME Released: 8/27/2013

Valid for credit through: 8/27/2014

processing....

  • Richard S. Isaacson, MD: Hello. I am Richard Isaacson. I am an associate professor of neurology and director of the Alzheimer's Prevention and Treatment Program at Weill Cornell Medical College in New York City. I would like to welcome you today to this program titled "Brain Glucose Hypometabolism, Ketosis, and Alzheimer Disease (AD): From Controversy to Consensus."

  • Slide 1.

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  • Joining me today are Stephen Cunnane, professor of medicine and physiology at the University of Sherbrooke, and former director of the Research Center on Aging, Sherbrooke University Geriatric Institute, Sherbrooke, Quebec, Canada; and Russell Swerdlow, professor of neurology and director of the University of Kansas Alzheimer Disease Center and the Kansas University Medical Center Neurodegenerative Disorders Program in Kansas City, Kansas. Welcome.

    Russell H. Swerdlow, MD; Stephen C. Cunnane, PhD: Thank you, Richard.

  • Slide 2.

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  • Dr Isaacson: The goals of this program are to discuss results of clinical research on brain glucose hypometabolism as a characteristic of AD; describe the rationale for therapies to address brain glucose hypometabolism; and compare and contrast strategies to induce ketosis to address brain glucose hypometabolism.

    Before we begin, I would like to note that this program may include discussion of treatment options that deviate from US Food and Drug Administration (FDA) recommendations. In addition, this program will include discussion of therapeutic strategies not approved by the FDA for use in the United States. At times during this conversation we will pause to ask a few polling questions. Your answers will help us develop future educational activities. Here is our first polling question.

  • Slide 3.

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  • I think all of us understand that AD is not only a growing public health concern but also a public health crisis, and perhaps even an emergency. I have had several family members affected, and I think most of our viewers, as well as most of the people in this room, have had either a friend or family member with AD.

    The costs associated with diagnosis and treatment for AD are staggering. Because age is the number-one risk factor for AD, and since baby boomers began turning 65 last year, AD will be an even greater burden on our healthcare system. Unfortunately, we have observed failures of recent clinical trials of disease-modifying therapies for AD. We are still searching for potential strategies to treat, or better yet reduce the risk of or even prevent the disease entirely.

  • Slide 4.

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  • The need for innovative approaches to AD has led us to look deeper into the potential causes of this condition. When I was in medical school, I was taught that amyloid and tau proteins were the major culprits causing AD. In 2013 and beyond, we are learning that such proteins may not be the cause of AD, but may in fact be a downstream effect of disease pathology. We will be talking about that in today's discussion.

    What causes the cognitive impairment, the memory loss, and the problems with executive dysfunction that are the hallmarks of AD? One exciting avenue of research that examines how the neurons in the brain use fuel to function is the area of brain glucose metabolism -- more specifically, the brain's reduced ability to use glucose as its primary fuel source.

    Let's begin by establishing a few facts about brain metabolism. The brain can use 2 different types of fuel for energy: one is glucose and the other is ketone bodies, also known as ketones. When the brain is unable to use glucose as its primary energy source, the problem is called brain (or cerebral) glucose hypometabolism.

    As I noted, most clinicians have been taught that AD and amyloid go hand in hand. But some experts -- including those on this panel -- wonder whether other pathophysiologic mechanisms are at work.

    Today, we are going to address several questions. The first is, what should we understand about AD pathophysiology and its relationship to brain metabolism?

    Dr Swerdlow: Science is still trying to get a good handle on this disease process. Certainly, one of the predominant views in the field is that amyloidosis is neurotoxic and is likely a major player in the pathogenesis of the disease. But it is not clear why amyloid beta (Aβ) is being deposited in the first place. What I can say is that the production of Aβ and the removal of Aβ are exquisitely regulated processes, and one of the processes that regulate Aβ is brain energy metabolism. It has been recognized for more than 30 years that brain energy metabolism is altered in the brains of people with AD. That has been demonstrated through a number of different approaches, both in vivo and in vitro, including fluorodeoxyglucose (FDG) positron emission tomography (PET) scans.

    Dr Cunnane: As you say, it has been established for at least 30 years that brain glucose metabolism is lower in areas of the brain that are directly involved in AD. The question has always been, is this a cause or an effect? Until recently, the thinking has been that if the neurons are dying, they are going to need less fuel. In that view, glucose hypometabolism is purely a consequence of the disease. However, there are emerging lines of evidence suggesting that a metabolic problem is also present in the neurons before the clinical symptoms start to develop.[1,2]

    Dr Isaacson: The audience for this program ranges from neurologists and other specialists to primary care providers. I would like to establish a baseline of knowledge for this wide range of clinicians. Russell, please tell us about the importance of ketones. Let's start by talking about infant brain metabolism.

  • Slide 5.

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  • Dr Cunnane: It is important to understand that ketones have a fundamental physiological role in the development of the brain. In the first year of life, glucose cannot supply the brain's energy needs. Instead, ketones are the primary source of fuel for the infant brain. Ketones are also very important in the development of the structure of the brain, including lipid metabolism. Cholesterol, for instance, is an extremely critical molecule in the brain, and most of the cholesterol in the brain is produced from ketones.

    Let me address an issue of terminology that may be a source of confusion. When we talk about ketosis, we are simply referring to the fact that the body can use ketones for fuel. There is concern in the medical community -- understandably so, perhaps -- that "ketosis" means the same thing as "ketoacidosis," which is a serious consequence of untreated diabetes. These 2 conditions are quite different. Ketosis refers to the nutritional and physiological role of ketones in low concentrations, while ketoacidosis is a condition in which metabolism is completely out of control and ketones are produced at much higher concentrations than can be achieved under other circumstances and are contributing to acidosis, which is harmful.

    Dr Swerdlow: When I was in medical school we were taught simply that the brain metabolizes glucose as the main energy substrate. That is largely true, but the picture is far more complex. Glucose is metabolized to a large extent in astrocytes, which then use the glucose in glycolysis and in feeding lactic acid to neurons, which use that as a respiratory fuel. So the situation is more complex. We have known for many decades that one of the alternative fuels that the brain can utilize are ketone bodies, which are basically what your brain uses to run under certain conditions, such as starvation.

    Dr Isaacson: Neurologists have used the ketogenic diet for a variety of conditions, such as pediatric epilepsy. But the use of a ketogenic diet as a strategy for AD is a new area that has not yet been explored.

    Even healthy, normal adults can have amyloid buildup. Similarly, there is a normal decline in glucose utilization with age. Genetic factors may be involved that further reduce brain glucose metabolism in AD. We are learning that mitochondrial dysfunction is also involved. What can you tell us about how mitochondrial dysfunction comes into the picture?

    Dr Swerdlow: The way that mitochondrial dysfunction manifests in AD is one reason why I believe that it may be a relatively upstream part of the process.[3,4] We see problems with the respiratory chain, not just in the brain but also in peripheral tissues. Mitochondrial deficits in patients with AD are probably not simply a consequence of neurodegeneration or even of Aβ production. Mitochondrial dysfunction is probably a reasonable target to go after if we hope to treat the symptoms of AD.

    Dr Cunnane: It is important to add that the mitochondria are the "furnaces" of the brain. They generate the heat and the energy that neurons need. Remember that 25% of our body's energy is used to support brain function. Accumulation of Aβ protein will stress some of these cells, causing injury and inflammation. Those cells will then need more energy. Amyloidosis competes for the energy that should be used to run normal cell functions, such as intracellular communication. The neuron is trying to fight off this pathological process at the same time. Oxidative stress undoubtedly contributes, and the neurons are trying to fight that process as well. Consequently there is a higher energy demand in the brain, and these other processes are also slowly contributing to neuroinflammation. This situation is probably established by the time we reach the age of 50 or 60. We do not yet know at what stage this becomes a critical factor or whether it is a critical factor in the development of cognitive problems such as Alzheimer dementia. The basic point here is that there are a lot of cellular processes competing for the available energy, and the mitochondria face challenges in trying to fuel the neurons and keep memory working properly.

    Dr Isaacson: What do we need to understand as practitioners about the relationships among type 2 diabetes (T2D), insulin resistance, insulin sensitivity, and brain fuel metabolism?

  • Slide 6.

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  • Dr Swerdlow: Certainly, there are links between T2D and AD.[5] People with T2D are at higher risk of developing AD, and several hypotheses have been proposed to explain this observation. For example, high insulin levels, such as those observed in people with insulin resistance, might prevent the brain from degrading Aβ protein, because the enzymes responsible for that function are too busy degrading insulin. But there are other possibilities as well. For example, there may be a systemic mitochondrial defect, or a problem with brain energy metabolism, or a problem in the peripheral tissues.

    Dr Cunnane: I would add that insulin is a critical hormone that decides which fuel is going to be used in the brain.[1] If you have not eaten in the last 6 hours and your blood glucose level is going down, then ketones are going to be produced along with fatty acids liberated into the blood. The brain is absolutely dependent on ketones as an alternative fuel to glucose. This is not the case with muscle, including the heart, or some of the other organs, which can use fatty acids. The brain's alternative fuel to glucose is ketones. The brain is the only organ that has that requirement. In T2D, glucose levels are elevated, so fuel availability is not the problem. The problem is that the cells that should be using the glucose are unable to do so. This is what we call insulin resistance. We always thought that the brain was not affected by insulin or by insulin resistance. However, in the past decade or so, it has become clearer that, in fact, one of the reasons why people with T2D appear to be more vulnerable to AD is because insulin appears to play a role in the brain that we are just beginning to understand.

    Dr Isaacson: These are common concepts that we have heard about in diabetes and other metabolic conditions, but it would appear that this concept is now being applied to brain function, and specifically to the pathophysiology of AD.

    Dr Swerdlow: There is mounting evidence that insulin-signaling pathways are downregulated in the brains of people with AD.[5] That is basically what we refer to as insulin resistance and has led some people to propose that perhaps AD might be thought of as "type 3 diabetes."[6]

    Dr Isaacson: Let's pause to ask another polling question.

  • Slide 7.

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  • Dr Isaacson: Can we reduce the risk of AD by intervening early, in the preclinical or presymptomatic stages? We know that changes in the brain of an individual with AD start 20 to 30 years before the diagnosis is made and long before symptoms start. Ix`f a member of my family develops AD at age 65 or 70, then I would want to take preventive steps in the presymptomatic stage, which would be in my 30s or 40s. Russell, how would you respond?

    Dr Swerdlow: The man in the office next to mine just turned 90 years old. He said, "If I'd known I was going to live this long, I would have taken better care of myself." We all want to age as well as possible. Obviously, we want our brains to age well too. There are many studies currently examining how we can slow down -- or even reverse -- brain aging. In my laboratory we are looking at interventions such as exercise, which we know is good for maintaining and improving muscle strength,[7] and caloric restriction,[8] which we know boosts bioenergetic metabolism in organs such as the liver and the brain. In general, we are finding that the best strategies are lifestyle related, such as physical exercise and particular dietary maneuvers.

    Dr Cunnane: This is the crux of the matter. Can we treat the problem before it becomes untreatable? It would be naive of us to suggest that there is a clear pathway to that outcome. It is also appropriate, however, to note that some strategies are encouraging and we should be pursuing those with randomized clinical trials. AD does not develop overnight. It is not an infection, where you are fine one minute and sick the next. It is a chronic, degenerative process like diabetes, high blood pressure, or cancer. There are processes that take quite a long time to develop and that can go on silently for some time. Nobody has yet conducted the long-term studies that would allow us to make firm recommendations regarding AD prevention, but we are taking steps in that direction. Promising results from randomized controlled trials suggest that this is worth exploring in a serious way. But it is going to require an investment, the right amount of time, and the right number of participants.

    Dr Isaacson: Absolutely. Just a few years ago, it was taboo to even say the words "Alzheimer disease" and "prevention" in the same sentence. Whether you use the term "treating preclinical Alzheimer disease" or "Alzheimer's prevention," I think we are finally now starting to understand that there are several low-risk interventions, grounded in evidence and balanced in safety, that we can apply as general recommendations.[9]

    In my clinical practice I take a fairly aggressive approach to prevention by trying to meet with several family members of my patients with AD. It has been said that what's good for the heart is good for the brain. I take that a step further. Russell, based in part on basic research by you and by other investigators, I place my patients on low-carbohydrate diets specifically aimed at lowering the risk for AD.[10] I have seen high compliance with these types of diets. I also advocate for the use of specific B vitamins. A recent randomized study showed that B vitamins -- folic acid, B6, and B12 -- can actually slow down the rate of hippocampal atrophy.[11] That is encouraging news, but much more research is needed before this strategy can be widely recommended.

    Dr Cunnane: As you noted, this is something that the whole family should have an interest in adopting. Even if AD did not exist, the lifestyle approaches that we are discussing are relevant to the prevention or management of cancer, diabetes, heart disease, and hypertension. In one sense, we should forget about AD per se, because we cannot be sure which biomarkers are going to lead us to the "holy grail" of AD prevention. What is good for other lifestyle diseases may have benefit for the development of clinically symptomatic AD as well.

    Dr Isaacson: I could not agree with you more. Physical exercise on a regular basis, stimulating mental activities, learning something new, taking on a new hobby, engaging yourself mentally and socially,[12] adhering to a Mediterranean-style diet[13] -- I think we have to use all of these lifestyle interventions to achieve the biologic principle of synergy.

    Dr Cunnane: One common denominator is that these types of interventions provide benefits with respect to insulin and the control of fuel metabolism. This gives us a clue about what avenues to pursue in a more aggressive therapy-based approach that can complement or be added to lifestyle changes.

    Dr Swerdlow: These are not abstract issues. AD increasingly affects many older adults, and many middle-aged adults are not practicing healthy lifestyle behaviors such as exercise, nutrition, and social engagement. There really is a practical application to all of this.

    Dr Isaacson: I try to take a realistic approach with my patients and their families. I tell them we do not have proof, we do not yet have an FDA-approved drug for the prevention of AD. Perhaps one day we will, but until that time, using a combination of these approaches is the best defense we have.

    Dr Swerdlow: Once we reach adulthood, brain function begins to decline. I sometimes explain it to my patients by saying that the "brain train" starts to come off the tracks. If I can extend that metaphor, the 2 factors that are the greatest determinants of when you will develop cognitive impairment are first, how far you are from the cliff -- from impaired memory and cognition -- and second, how fast you are heading there; that is, what factors are contributing to cognitive decline. The lifestyle interventions we're discussing are the best options we currently have to manipulate that trajectory; to keep the train on the tracks and to slow down its progress.

    Dr Isaacson: What do we need to understand about inducing ketosis as a strategy for addressing brain glucose hypometabolism?

  • Slide 8.

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  • Dr Swerdlow: As you know, starvation can induce ketosis. That is not what we are talking about here. The most natural way to induce ketosis is to reduce carbohydrates and increase intake of fat and protein. For decades, neurologists have used the ketogenic diet to treat conditions such as epilepsy. During the induction phase of the Atkins diet, people can develop ketosis. Certainly, those methods are much easier and gentler than starving oneself. And there is some evidence that these diets are associated with better lipid profiles and reduction in the metabolic syndrome.

    Dr Cunnane: It is important to state that ketosis is not a process that one gets involved with lightly. A low-carbohydrate diet means eating very limited amounts of bread, pasta, rice, and potatoes; all of those familiar carbohydrates that are very high in starch, which increases glucose levels. People have to appreciate the implications of attempting a major change in their diet. It is easy to make a list of what you are trying to achieve, but it is not always so easy to follow that list. To support this effort, one alternative is to use a supplement that can produce a similar ketogenic effect, such as what has been seen with medium-chain triglycerides; this has been shown to have some efficacy in childhood epilepsy. There are preliminary data suggesting that it also works in cognitive decline.[14,15]

    We mentioned this earlier, but I think it is worth repeating. It is critical for neurologists, for general physicians, and for the public at large to appreciate that nutritional ketosis achieved through a dietary approach -- whether through caloric restriction, a low-carbohydrate diet, or use of a medium-chain triglyceride supplement -- is not the same as diabetic ketoacidosis. The latter is a pathological condition that no one wants and of which physicians are very aware. In contrast, nutritional ketosis is something that can be sustained and is not dangerous.

    Dr Isaacson: In my practice I often place my patients on a comprehensive Alzheimer-type diet where I reduce the overall amount of carbohydrates, but I do not push them to the point of ketosis. Tell me about your experience. You are doing a trial now that is focused on trying to get people onto a ketogenic diet.

    Dr Swerdlow: Yes. A ketogenic diet will raise the level of ketone bodies and switch brain fuel utilization toward things like β-hydroxybutyrate and acetoacetate, which are the 2 major ketone bodies.[16] We still need to learn how palatable that diet is to patients, but it appears to be a practical one that is easily followed. Will patients with AD or its frequent precursor state, mild cognitive impairment, be able to adhere to such a diet? Will they be able to maintain stable ketosis, or will they abandon the diet because it is just too demanding? Or will starting after patients when they are symptomatic be too late? Perhaps these diets will be shown to be more efficacious in prevention.

    Dr Isaacson: I think your research is going to help clinicians to be informed about best strategies to use and the success rates that can be achieved. I am excited to see the results. I think there are other ways, as you said, Stephen, to use an additional medium-chain triglyceride.

  • Slide 9.

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  • There is a new prescription medical food called Axona® that supplies a medium-chain triglyceride, caprylic triglyceride, in a drinkable formulation. This strategy increases ketosis regardless of whether someone has carbohydrates on board, or is in mini-fast. However, the amount of ketones that are generated by this product is very small -- about 1/1000 of the level of ketones that cause ketoacidosis in patients with diabetes.[17]

    Dr Cunnane: I think use of caprylic triglyceride is a practical solution to a challenging problem. You want to prevent cognitive deterioration in the elderly, but using a dietary approach in itself can be challenging. The fact that a medical food like caprylic triglyceride is available is a major step in the right direction. Also, its use does not depend on your insulin status. If you have a diabetic condition, your insulin levels are probably elevated.

    If you have a tendency toward obesity or type 2 diabetes, chances are you have already dealt with the issue of dietary modification. Clinicians are rightly concerned about adding fat to the diet, and a ketogenic diet by definition is a high-fat diet. But it is important to stress that not all oils and fats are bad for you. Children on the ketogenic diet for 2 years for epilepsy control do not get obese.The blood lipids in people on a ketogenic diet are generally lower, so just because a ketogenic diet is high in fat does not mean that you are going to become obese. This is a common misunderstanding about the nature of this type of diet. In addition, cholesterol is an important lipid that is required for neuronal integrity and repair. Thus, fats play an important role in maintaining functioning in the central nervous system.

    Dr Isaacson: Caprylic triglyceride comes as a powder that you mix with water, another liquid, or a soft food. Typically it is consumed with breakfast or lunch, whichever meal is larger. In terms of safety and efficacy, there have been some preliminary trials, a phase 2b trial, as well as an ongoing phase 3 randomized clinical trial.[14,15,18] I should note that this approach can be used concomitantly with other FDA-approved medications and other lifestyle approaches, such as exercise, social engagement, stress reduction, and diet.

    Could you review the clinical trial data regarding other approaches to reducing carbohydrates and inducing ketosis?

  • Slide 10.

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  • Dr Swerdlow: Surprisingly, there are very little. There is 1 published study by Krikorian et al looking at a low-carbohydrate diet used to induce ketosis in patients with mild cognitive impairment. It was a small pilot randomized study with 23 people that showed a signal of some cognitive benefit.[19]

    Dr Isaacson: I thought it was interesting in that study that not only was a cognitive benefit demonstrated, but also that insulin sensitivity improved. Fasting glucose was reduced, and even waist circumference was reduced.

    Dr Swerdlow: In some people it seems paradoxical that you can ingest more fat and still lose weight and your cholesterol goes down, but if you do it correctly, that is generally what happens.

    Dr Cunnane: We have to be careful not to confuse a high-fat diet with a high-energy diet. Most people have high energy intake, which often means a diet high in fat and refined carbohydrates, accompanied by a sedentary lifestyle. The high-fat ketogenic diet removes almost all refined carbohydrates. Fats alone are not going to make you gain weight but they may improve other cardiovascular outcomes apart from cognition, as seen in the Krikorian pilot study we just mentioned.

    Dr Isaacson: We have some practical clinical experience in putting people on low-carbohydrate diets and I think your study is going to define tolerability as well as compliance. It is going to be extremely important to inform the field. What has been your clinical experience with caprylic triglyceride? In which patients would you use it?

    Dr Swerdlow: It is indicated for use as a medical food for people with a diagnosis of AD, which means it is not quite a supplement and it is not quite a prescription medicine. It is designed as a relatively benign way to induce ketosis in people who drink it.

    There are side effects associated with it, including gastrointestinal upset, stomach cramping, and gas. These side effects tend to diminish or go away over time, and people generally tolerate the product.

    Dr Isaacson: In my clinical practice I take the "start low and go slow" approach, just as I do with medicines like cholinesterase inhibitors. We start at a low dose and titrate up slowly. The same thing holds true with caprylic triglyceride. In the clinical trial mentioned earlier, 80% of the subjects were already taking an AD treatment -- one of the FDA-approved cholinesterase inhibitors or memantine, an N-methyl-D-aspartate (NMDA) antagonist -- so caprylic triglyceride can be used in combination with any one of the FDA-approved AD drugs.[19] It is worth emphasizing again that caprylic triglyceride is not an FDA-approved drug, but it is an FDA-approved medical food intended for the clinical dietary management of the metabolic processes associated with mild to moderate AD. It requires a prescription from a physician.

    Dr Cunnane: It is important at this stage to discuss mechanistic issues. Observing a clinical benefit is obviously the major goal, but can we maximize or optimize that effect? Could we simplify how this is done? Is there something that is more effective than a ketone-producing product like caprylic triglyceride?

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  • My group has been working on PET imaging of the brain using both ketones and FDG, which is used to measure brain glucose uptake. What is interesting about the comparison of healthy elderly individuals to age-matched cases with AD is that the AD cases have further deficits in brain glucose uptake, but they do not have further deterioration of brain ketone uptake. This suggests that the brain of the individual with AD is still able to use these ketones, which is a critical step in trying to make a logical case that the neurons are not dead. That may be the reason they are able to respond and why some of the decline that one would normally expect to see over 6 to 12 months is not occurring. One assumes, of course, that the neurons are able to function, but this gives us a further window into the process by being able to demonstrate that the deficit in glucose uptake is not observed with the alternative fuel, the ketones.

    Dr Isaacson: We have had an informative discussion today. It has been a pleasure to speak with both of you. I think we have been able to clarify that the pathophysiologic puzzle of AD is not just Aβ and not just tau protein, but that there may be a bioenergetic mechanism that is causing these proteins to build up. What are your closing thoughts?

  • Slide 12.

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  • Dr Cunnane: I think the field is at a critical crossroads at the moment. There has been a great emphasis on the fear associated with this diagnosis. There has been a lot of dashed hope that therapeutics aimed at Aβ were going to be a solution, and that may yet turn out to be the case.

    One of the stumbling blocks in this process is that we have forgotten about the fact that the neuron is like a Formula 1 race car. It is an extremely high-performing cell that constantly requires a lot of fuel. If you use a low-quality fuel, then the fuel filter can get clogged. What we are trying to do is unclog the fuel filter and allow the neuron to perform at its full capacity. Doing so perhaps will support the action of drugs that target Aβ. I think we'd agree that it is important to take a multidimensional approach and not put all of our emphasis in one particular direction. If we can show results, we can give people legitimate hope that there are ways to intervene so as to reduce the risk of further cognitive decline. This is an important strategy and an important step in that direction, and it may be that preventing or treating AD may require a "cocktail" or several different drugs that target several different mechanisms.

    Dr Swerdlow: Brain bioenergetics clearly change with advancing age, and they change even more in AD. This is a problem that we can try to address. What we may be seeing here is the beginning of a new era in what I would call bioenergetic medicine, which addresses the dilemma of repairing or reversing problems with brain energy metabolism.

    Dr Isaacson: Thanks. Here is our final polling question.

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    Slide 13.

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  • Let me conclude by summarizing the main ideas that we discussed today. Our understanding of AD pathophysiology is evolving. We have come a long way, but we still need more research and more randomized trials in this area. Low-risk therapeutic interventions may yield benefit along the spectrum of preclinical AD; mild cognitive impairment; and mild, moderate, or severe AD. Further study is warranted to prove or disprove some of these concepts.

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    Slide 14.

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  • I want to thank our panelists, Stephen and Russell, for this fascinating discussion. I am sure we will be hearing more about this topic in the months and years to come.

    Thank you for participating in this activity. You may now take the CME post-test by clicking on the "Earn CME Credit" link. Please also take a moment to complete the program evaluation that follows. Thanks very much.

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    Slide 15.

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This transcript has been edited for style and clarity.

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