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Can The Brain Use Ketones

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Ketone Bodies May Support Metabolism Besides Being A Substrate

Using Ketones for Brain Function | Dr. Boz

The theory related to the fuel crisis seen with neurodegenerative disease is summarised in , which also demonstrates the proposed protective mechanism of ketone bodies, especially BHB.

Vicious circle of energy crisis in neurodegenerative disease. The proposed effects of beta-hydroxybutyrate on disease mechanisms are illustrated in green, demonstrating an inhibition of oxidative stress, neuroinflammation and mitochondrial dysfunction together with a facilitated ketone oxidation, which results in at least a partially restored metabolism.

Ketone Bodies And Cognition In Alzheimers Disease And Related Conditions

A number of approaches to increase ketone body availability have been applied in elderly individuals and in diseases affecting cognition. These approaches include both acute interventions of BHB infusion or a single meal/drink of MCFA , and also long-term treatments with continued MCFA supplementation as an add-on to the regular diet or complete conversion to a ketogenic diet . A predominance of studies has been conducted in patients with mild cognitive impairment and AD and apply the MCFA supplementation approach to achieve ketonemia. Hence, future studies implementing other ketogenic approaches will strengthen the evidence of a ketone-induced cognitive improvement.

In agreement with the above studies, Fortier et al. recently published the cognitive outcomes from the BENEFIC trial, a 6 month placebo-controlled trial of MCFA supplementation in patients with mild cognitive impairment . The study found significant improvements in tests related to memory , executive function , and language , which may be related to the improved total energy metabolism in the brain found in the first part of the trial .

Apart from cognition, a number of paraclinical features have been studied in neurodegeneration. For example, the notion of disturbed cerebral fuel metabolism in neurodegeneration is far from recent in 1960, Lassen et al. described a decreased cerebral oxygen metabolism in people with presenile dementia, a finding corroborated by Lying-Tunell et al. in 1981 .

Ketones In Clinical And Experimental Hie

Ketone levels in infants with HIE are less well understood, other than in a small group of patients described by Reinke et al. and Ahearne et al. . In cord blood from asphyxiated infants who did not have evidence of significant clinical HIE, increased levels of BHB were seen compared to in healthy controls. Similar to in the rat after unilateral HI, ketogenesis may be initially upregulated during or after asphyxia due to increased glucose utilization and the release of catecholamines and cortisol, both of which can increase lipolysis and fatty acid delivery to the liver. By comparison, infants with severe HIE were found to have decreased levels of both acetone and BHB, and low BHB was part of a metabolite model that predicted the infants in the cohort that later died . The timing and mechanism of any changes in ketone production after HIE, as well as any associations with severity of injury, therefore remain to be fully elucidated.

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Deteriorating Brain Glucose Uptake In Insulin Resistance

The metabolic profile of the older cohort described above was moderately well matched to the younger group but some parameters did differ significantly, i.e., body-mass index, blood pressure, homocysteine, and some measures of glucose homeostasis were not identical and could have adversely influenced brain glucose metabolism . However, it is difficult to find older people in whom the metabolic profile is strictly within the same limits as adults < 35 years-old. Mild insulin resistance seems to be a common feature of aging, but it is by no means limited to the older population. The importance of this point became clear to us when we studied young women with mild insulin resistance due to PCOS. They had a brain glucose uptake deficit in the superior and middle frontal cortex of about 14%, i.e., a profile resembling that of people in their 70 and 80s . PCOS is a multi-factorial endocrine disease involving not only mild-moderate insulin resistance but also infertility and hyperandrogenism. The mild insulin resistance was of particular interest to us because it is associated with increased risk of AD in middle-aged and older adults .

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References

1. Parrott MD, Greenwood CE. Dietary Influences on Cognitive Function with Aging. Ann N Y Acad Sci. 2007 Oct 1 1114:38997.

2. Greenwood CE, Winocur G. High-fat diets, insulin resistance and declining cognitive function. Neurobiol Aging. 2005 Dec 26 Suppl 1:425.

3. DAnci KE, Watts KL, Kanarek RB, Taylor HA. Low-carbohydrate weight-loss diets. Effects on cognition and mood. Appetite. 2009 Feb 52:96103.

4. Kang HC, Chung DE, Kim DW, Kim HD. Early- and Late-onset Complications of the Ketogenic Diet for Intractable Epilepsy. Epilepsia. 2004 Sep 1 45:111623.

5. Wang X, Lin X, Ouyang YY, Liu J, Zhao G, Pan A, et al. Red and processed meat consumption and mortality: dose-response meta-analysis of prospective cohort studies. Public Health Nutr. 2016 Apr 19:893905.

6. Kahn HA, Phillips RL, Snowdon DA, Choi W. Association between reported diet and all-cause mortality. Twenty-one-year follow-up on 27,530 adult Seventh-Day Adventists. Am J Epidemiol. 1984 May 119:77587.

7. Orlich MJ, Singh PN, Sabaté J, Jaceldo-Siegl K, Fan J, Knutsen S, et al. Vegetarian Dietary Patterns and Mortality in Adventist Health Study 2. JAMA Intern Med. 2013 Jul 8 173:12308.

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Can The Brain Use Ketones Instead Of Glucose

The brain surely can function and perform on ketones almost. Glucose is usually the brains main source of energy and fuel. The body and muscles use fat as a source of energy but brain cannot use fat to function. However, it uses ketones when sugar and insulin levels are low. When glucose levels are too low, the liver naturally produces ketones.

Brain Networks Destabilize With Age

Across the life span measured by Cam-CAN, cognitive acuity declined with age, as measured by the standard clinical instrument used to assess dementia, the Mini-Mental State Examination . Cam-CAN and Leipzig resting-state datasets show that increased age, in turn, was associated with destabilization of brain networks . This effect was driven primarily by the dynamics of three resting-state functional networks : auditory , higher visual processing and basal ganglia . LASSO regression with instability of the 12 resting-state networks as predictor variables and age as the predicted variable identified these three networks with high selectivity , assigning all other networks zero weight.

    ALFF, a general measure of brain activity, was increased for participants on the ketogenic diet compared to their standard diets . This remained true for resting state, as well as during motor and spatial navigation tasks. Resting state and motor tasks were of 10 min duration. Spatial navigation shows the first 10 min and then an additional 30 min, for 40 min total. This was done to assess fatigue effects over longer periods of time. Comparing symmetry over time between shifts from lower- to higher-activity states versus shifts from higher- to lower-activity states, both the ketogenic and fasting conditions showed a mean of zero bias , whereas the standard diet condition showed the brain switching from high- to lower-activity states .

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    Glycogen Production In Astrocytes

    The major energy reserve in the brain is glycogen, a macromolecular storage form of glucose . Found mostly in astrocytes , glycogen is a dynamic participant in brain activity and is regulated by neurotransmitters. Dysregulation of glycogen turnover may cause severe consequences, e.g., Lafora disease with progressive neurodegeneration and epilepsy leading to death in early adulthood . During intense brain activity, glycogen converted to lactate and released from astrocytes can be used by neurons as mitochondrial fuel. Meanwhile, rapid glycogenolytic generation of ATP may be important for astrocytic energy demands , and thus glycogenolysis, by reducing the astrocytic requirement for blood-borne glucose, can spare an equivalent amount of glucose for neuronal utilization . The estimated glucose equivalent of glycogen concentration in astrocytes is up to 40100 mM. Considering the high rate of glycogenolysis, the amount of glucose that can be released via glycogen breakdown is very significant . Unfortunately, glycogen levels in the human brain during KD have yet to be investigated. In rats, one study reported increased inbound glucose under KD, while no change in glycogen content was found in another study or glycogen was decreased . Carbohydrate intake does not affect brain glycogen content, while in both muscle and liver it does significantly correlate with glycogen levels .

    Who Shouldnt Try A Keto Diet For Brain Health

    Ketone Body Metabolism | Ketolysis | Transport, Absorption and Catabolism

    Before trying out a new diet, its always best to check with your healthcare provider first. This is especially true if you already have a health condition, or are taking medication.

    The ketogenic diet may cause your blood lipid profile to change a bit. Kids following a ketogenic diet for epilepsy saw changes in their total cholesterol, triglycerides, and LDL cholesterol levels.

    While the high-fat diet and heart disease myth has been adequately debunked at this point, individual biochemistry always needs to be taken into account.

    Another side effect that can come along with starting the ketogenic diet is constipation. If you already have severe constipation, you definitely want to get guidance in starting the keto diet. Typically, however, adding more fiber and making sure youre hydrated can resolve the constipation that accompanies keto.

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    Keto Supplement Safety Considerations

    Several trials that have examined the safety and tolerability of keto supplements conclude that exogenous ketones are generally safe, although they may have certain side effects. Exogenous ketone and MCT supplements have been associated with various symptoms, including:

    • Constipation
    • Headaches

    The severity of adverse effects depends on the supplement dose taken. Medical observation is advised for regular consumption of exogenous ketones.

    The Brain Can Run On Ketones Almost

    When you are on a keto diet, or fasting, your brain can switch from using glucose as its main fuel source to using ketones. There are however portions of the brain that do require glucose for function. The brain will use some of the carbohydrates consumed on a ketogenic diet and the rest will be produced through gluconeogenesis in the liver. During gluconeogenesis, the liver will create glucose using amino acids from protein. Glucose can also be created through gluconeogenesis by using the backbone of fatty acids, glycerol. This process ensures that the portions of the brain that rely on glucose will have their preferred energy substrate in times of fasting or very low carbohydrate intake.

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    How The Keto Diet Affects The Brain

    A low carbohydrate diet is a diet where only 5 to 30 percent of your total caloric intake comes from carbohydrates. There is plenty of research to suggest that this restrictive diet can free your brain to do more. The brain needs massive amounts of nutrients to function properly, and it typically gets those from carbohydrates. However, carbohydrates make you slow and the preferred energy source for optimal brain functioning seems to be ketones.

    Ketones And Critical Illness

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    The major illness associated by intensive care physicians with ketosis is diabetic ketoacidosis. Outside diabetic ketoacidosis, ketone measurement is not routinely performed and has been largely used as a research tool to quantify cellular redox status. The arterial ketone body ratio is utilized to reflect the mitochondrial redox status of hepatic cells and may reflect cellular energy status in a number of conditions including hemorrhage, hypoxia, sepsis and hepatic resection . The AKBR reflects the cellular NAD+/NADH ratio, which cannot be measured directly and is linked to the phosphorylation potential of the cell . In critically ill patients, the entry of acetyl CoA into the tricarboxylic acid cycle is limited. Acetyl CoA consequently combines with another molecule of acetyl CoA to form acetoacetic acid, which in turn is converted to BHB leading to an altered NAD+/NADH ratio and a decreased AKBR . A reduced AKBR is therefore a sign of an inefficient tricarboxylic acid cycle. The AKBR has also been used as an indirect marker of the hepatocellular functional status as the predominant site of metabolism of the ketones is in the liver.

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    Medium Chain Fatty Acids As A Source Of Ketones

    Ketones are produced by -oxidation of fatty acids. -oxidation is mainly hepatic but may also occur in the gut and brain, especially during early development . The substrate fatty acids for ketogenesis may be short-, medium- or long-chain fatty acids and may originate from the diet or from fat stores in adipose tissue. In adults, long chain fatty acids stored in fat or consumed as dietary triglycerides are the primary source of carbon for ketogenesis, but in the breast-fed infant, MCFA in milk are the most important source of carbon for ketogenesis . MCFA from breast milk can be stored in infant fat so once breast-feeding has terminated, stored MCFA can still be liberated to provide ketones . Coconut and palm oil are unusual amongst common dietary oils in that they contain some MCFA , so these oils are a simple, economical and well-accepted way to consume MCFA.

    Key points linking medium chain fatty acids, ketones and normal infant brain development.

    Issue Is Excessive Cataplerosis An Impediment To Successful Keto

    In addition to generating ATP, the citric acid cycle also has a key role in providing intermediates for several brain molecules including the neurotransmitters, gamma-aminobutyric acid and acetylcholine. The use of intermediates in the citric acid cycle to make molecules other than ATP is known as cataplerosis . Cataplerosis is usually balanced by anaplerosis, which is the net contribution of carbon from various sources to synthesize molecules derived from intermediates in the citric acid cycle. Glucose and oxaloacetate are anaplerotic so when both are insufficiently available, cataplerosis rapidly depletes the citric acid cycle . Unlike glucose, glutamine, pyruvate and precursors to propionyl CoA, the four carbon ketones do not contribute any carbon to anaplerosis . Indeed, ketones are probably cataplerotic in part because they increase citric acid cycle activity . Hence, glucose itself or an alternative anaplerotic substrate is essential in order to metabolize ketones, especially as ketosis becomes more extreme.

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    Issue Is Mitochondrial Function Impaired Early In Ad

    The bulk of the ATP needed during energy metabolism is produced by oxidative phosphorylation in mitochondria. Glucose can also produce some ATP via glycolysis, a process occurring outside mitochondria, whereas ketones produce ATP uniquely via oxidative phosphorylation. Mitochondrial damage and increased production of reactive oxygen species have been proposed to underlie beta-amyloid accumulation and cognitive deterioration in AD . Ketone catabolism is entirely mitochondrial, so normal whole body ketone oxidation in older humans argues for largely intact mitochondrial function in reasonably healthy older people. Normal brain ketone metabolism in AD also suggests that the enzymes of mitochondrial oxidative phosphorylation in the brain continue to function relatively normally, at least early in AD. Hence, early in AD, the problem with brain glucose metabolism is not necessarily at the mitochondrial level but possibly more because of lower glycolysis to acetyl CoA . Lower production of acetyl CoA would impair neuronal function thereby accounting for the well-known observation of lower glucose transport into the brain in AD. Oxidative damage to mitochondria and mitochondrial dysfunction would also tend to increase.

    Ketone Bodies Have Pleiotropic Neuroprotective Effects

    Your Brain on Ketones Alzheimer’s, Memory & MCT

    Due to their pleiotropic physiological effects , as well as the fact that the neonatal brain is adapted to uptake and utilize ketone bodies, ensuring adequate ketosis in infants after HIE has the potential to mitigate many of the pathological processes associated with HI brain injury. However, as the process of endogenous ketogenesis takes many hours to develop, achieving elevated blood ketone levels within the 6-h latent phase of HI brain injury is not feasible through endogenous ketosis. This leads to the hypothesis that exogenous ketones could be delivered soon after an insult to rapidly induce ketosis to preserve cellular function during the latent and secondary phases of injury. Due to their potential neurotrophic action and function as synthetic precursors, exogenous ketones may also contribute to longer-term repair mechanisms beyond the traditional therapeutic window.

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    Can The Brain Use Ketones Choosing The Optimal Brain Fuel

    With the rise of the ketogenic diet, there has been a significant debate over which form of biological fuel helps your brain run optimally.

    For the vast majority of your life, your brain oxidizes glucose for energy. When you eat a low-carbohydrate diet or fast for extended periods of time, your liver can convert stored fatty acids into ketone bodies to be used as a secondary fuel.

    In short periods, like those found in intermittent fasting, the evidence suggests that these ketone bodies can actually have a strong, beneficial effect on certain tissues.

    However, in the ketogenic diet, which is designed to put your body in a state where your brain oxidizes primarily ketone bodies, there can be some unwanted long-term side effects.

    In this article, well discuss some of the science behind these different fuel sources, as well as the benefits of ketosis in small instances, like intermittent fasting.

    Then, well explain why the ketogenic diet though it may have some immediate health results is actually not ideal for your health in the long term.

    Regional Brain Ketone Uptake In Ad

    The aforementioned clinical reports of a cognitive benefit of MCT in AD are still preliminary and require replication on a larger scale. Nevertheless, they provisionally support the hypothesis that a regional brain glucose deficit contributes to impaired cognition associated with aging and that this deficit can at least in part be bypassed by ketogenic treatments. A core element of this interpretation is that brain cells and/or networks that were previously dysfunctional can start to function more normally again once they are provided with more fuel, i.e., they were starving or exhausting but not dead otherwise this cognitive improvement would not be possible.

    Acetoacetate is the ketone that actually enters the mitochondria and is catabolized to acetyl CoA. Since synthesis of 11C-AcAc is easier than for 11C–HBA , we chose 11C-AcAc as our brain ketone PET tracer. In our PET protocol, 11C-AcAc is infused first followed by a wash-out period and then FDG is infused . A period of time equivalent to four half-lives of 11C occurs between the 11C-AcAc infusion and the acquisition of the FDG image. This dual tracer technique allows for a quantitative same-day comparison of brain uptake of glucose and ketones thereby avoiding the unnecessary inconvenience to the participant of returning a second time, as well as reducing the biological variability between PET scans done on different days. This dual tracer protocol has been applied in human and animal studies .

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