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MEDIUM CHAIN TRIGLYCERIDES, Ketone Esters, and ketogenic diets FOR ALZHEIMER’S and other disorders

MEDIUM CHAIN TRIGLYCERIDES, Ketone Esters, and ketogenic diets FOR ALZHEIMER’S and other disorders. Mary T. Newport MD December 12-14, 2012 Fellowship in Anti-Aging, Regenerative and Functional Medicine – Module 15. Alzheimer’s Facts and Figures. According to the Alzheimer’s Association*:

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MEDIUM CHAIN TRIGLYCERIDES, Ketone Esters, and ketogenic diets FOR ALZHEIMER’S and other disorders

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  1. MEDIUM CHAIN TRIGLYCERIDES, Ketone Esters, and ketogenic diets FOR ALZHEIMER’S and other disorders Mary T. Newport MD December 12-14, 2012 Fellowship in Anti-Aging, Regenerative and Functional Medicine – Module 15

  2. Alzheimer’s Facts and Figures According to the Alzheimer’s Association*: • 5.4 million people in the USA alone have Alzheimer’s (AD) and predicted to be 15 million in USA by 2050, and100 million worldwide • 1 in 8 older Americans has AD • More than 200,000 under age 65 have “early onset” AD • Nearly half of people over age 85 have AD • While deaths from stroke, heart disease, and certain cancers declined between 2000 and 2006, deaths from AD increased by 47.1% • Cost of care to government and businesses estimated $200 billion and equivalent of $210 billion unpaid caregiving *2012 Alzheimer’s Disease Facts and Figures Report from Alzheimer’s Association

  3. Plaques and Tangles 100 billion nerve cells. 100 trillion synapses. Dozens of neurotransmitters. Brain tour from Alzheimer’s Association, alz.org. Blennow K, MJ de Leon, H Zetterberg. “Alzheimer's disease.” The Lancet, Vol. 368 No. 9533 (2006): 387 - 403

  4. PNAS 2008 105 (9): 3171-3172 4 – 8 month old WT 11.9 month old APP23 12 month old APP23 18 month old WT 18 month old APP23 18 month old APP23

  5. Beta Amyloid PET Scan • Alzheimer's disease on the horizon? PET scans revealed beta-amyloid plaque in the brains of three Alzheimer's disease patients (left) and three normal controls (right). The yellow indicates high uptake of a label that targets beta-amyloid plaque, and the red indicates medium uptake. Dan Krotz. “New Clue in the Search to Predict Alzheimer’s Disease.” Berkley Lab News Center, December 16, 2008

  6. Brain metabolism and Alzheimer’s In 1970, Dr. Siegfried Hoyer reported decreased glucose levels & lower cerebral metabolic rate in brains of some people with dementia. By 2004, proposed decreased brain metabolism results in diminished production of acetyl CoA and ATP, required for synaptic activity and plasticity. Siegfried Hoyer. “Brain metabolism and the incidence of cerebral perfusion disorders in organic psychoses.” Deutsche Zeitschrift für Nervenheilkunde 1970 ,197 (4): 285-92 Hoyer S: Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications. Adv Exp Med Biol 2004, 541:135-152

  7. Brain metabolism and Alzheimer’s In 1991, Hoyer reported that: • There is a shift in the types of fuel used by the brain in people as they age that is even more prominent in people with AD • Young normal people use fuel in the cerebrum in ratio of 100:1 of glucose to alternative fuels • Elderly persons without Alzheimer’s, this ratio is 29:1 • Early stages of Alzheimer’s this ratio is 2:1 • Suggested fuel for brain cells must come from alternative fuels, such as fatty acids and amino acids Hoyer S. “Abnormalities of glucose metabolism in Alzheimer’s disease.” Annals New York Academy of Sciences Vol. 640 (1991): 53-58 

  8. Alzheimer’s is “Type 3 Diabetes” Explosion of research into the relationship between AD and brain glucose metabolism in 1990’s and beyond. In 2005, De la Monte and Wands looked at brains of persons with advanced AD who did not have type 1 or 2 diabetes: • Levels of insulin and factors related to making and using insulin are greatly reduced. • All of the signalling pathways involved in the use of energy are abnormal. • The functioning of mitochondria is abnormal. • Coined term “type 3 diabetes” to describe insulin deficiency and insulin resistance in AD brain De la Monte SM, JR Wands. “Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer’s disease.” Journal of Alzheimer’s Disease Vol. 7 (2005): 45-61

  9. Alzheimer’s is “Type 3 Diabetes” In 2008, de la Monte and Wands looked at various stages of AD brains in persons without type 1 or 2 diabetes: • Loss of insulin and neurons with insulin growth factor receptors begins early in the disease. • This worsens with each stage of the disease until it is very severe and occurs throughout the brain in most severe cases of AD. • Suggest that therapies for type 1 or 2 diabetes may be beneficial. • Intranasal Insulin • Metformin or other medications for type 2 diabetes De la Monte SM, JR Wands. “Alzheimer’s disease is type 3 diabetes – evidence reviewed.” Journal of Diabetes Science and Technology, Vol. 2 No. 6 (November 2008): 1101-1113

  10. FDG-PET scans show decreased glucose uptake NORMAL BRAIN ALZHEIMER’S BRAIN

  11. Alternative Fuels for AD • Glucose is the primary and preferred fuel for most cells, including brain. • Humans are programmed by evolution to switch to use of alternative fuels during starvation when glucose stores have been used up • Amino acids (Gluconeogenesis) • Fatty acids • Ketones • Lactate • Supplying an alternative fuel could bypass problem of insulin deficiency and insulin resistance in AD brain

  12. O. E. OWEN, A. P. MORGAN, H. G. KEMP, J. M. SULLIVAN, M. G. HERRERA, AND G. F. CAHILL, JR. “Brain Metabolism during Fasting” The Journal of Clinical Investigation Vol. 46, No. 10, 1967 First report of ability of brain to use ketones as fuel • Obese nurse given only water, vitamins, and salt tablets for a period of forty-one days. • Sampled blood from catheters in arteries and veins around her brain and liver. • Her brain survived this lengthy period of starvation by using ketones and by greatly reducing the use of glucose. • 2/3 of fuel used by her brain was provided by the ketone bodies beta-hydroxybutyrate and acetoacetate

  13. Diagram from: Oliver E. Owen. “Ketone Bodies as a Fuel for the Brain during Starvation,”Biochemistry And Molecular Biology Education Vol. 33, No. 4, 2005:246–251 Overnight in normal people: glucose 100% of fuel Starvation: Ketones about 2/3 of fuel

  14. Diagram from: Oliver E. Owen. “Ketone Bodies as a Fuel for the Brain during Starvation,”Biochemistry And Molecular Biology Education Vol. 33, No. 4, 2005:246–251 FIG. 3. Concentrations of ketone bodies and free fatty acids during starvation in humans. Values are shown as the means S.E. Ketone bodies undergo the greatest changes of all fuels during total starvation.

  15. 3 obese college students starved until β-OH B levels increased Given insulin to drive blood glucose into hypoglycemic range Developed none of usual symptoms of hypoglycemia: Brain is protected from hypoglycemia by ketone bodies. Diagram from: Chapter 26 - Alternative Fuel Utilization by Brain, George F. Cahill, Jr. & Thomas T. Aoki from Cerebral Metabolism and Neural Function (1980)

  16. Ketone Bodies • Dietary maneuvers can produce ketosis: • Starvation or fasting • Ketogenic diet • Medium chain fatty acids (MCFAs) absorbed directly • into portal vein and converted in liver to ketone bodies • Ketone esters, 1,3-D-Butanediol SS Bergen, Jr., Hashim SA, VanItallie TB “Hyperketonemia induced in man by medium-chain triglyceride,” Diabetes Vol. 15 No. 10 (1966): 723-725

  17. ATP Adapted by Joanna Newport

  18. KETOGENIC DIET • Reported positive effects of ketogenic diet: • Epilepsy • Alzheimer’s disease • Parkinson’s disease • Lou Gehrig’s disease (ALS) • Traumatic brain injury and stroke • Oxygen toxicity • Glioblastoma • Weight loss

  19. Ketones Protect NeuronsDr. Richard L. Veech • “Addition of 4 mmol D-b-hydroxybutyrate protected cultured mesencephalic neurons from MPP1 toxicity [Parkinson’s model] and hippocampal neurons from Ab1–42 toxicity [Alzheimer model].” • “Ability of ketone bodies to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases.” • “Ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.” Y Kashiwaya, T Takeshima, N Mori, K Nakashima, K Clarke, and RL Veech, “D-b-Hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease,” PNAS May 9, 2000, 97(10): 5440-5444

  20. Ketone Ester • Richard L. Veech, MD, D Phil, NIH, Rockville, MD, began developing ketone body product in late 1990’s • Filed first patent application to develop therapeutic ketone body in 1998. • After at least a dozen variations, successfully synthesizes an ester of (R)-3-hydroxybutyrate for oral or IV administration around 2006 • Can achieve levels equivalent to those that occur in ketogenic diet and in starvation without toxicity • Series of hypothesis papers proposing use for treatment of AD, other neurodegenerative diseases and traumatic brain injury • Parkinson’s study imminent “Hypothesis Paper:Ketone Bodies, Potential Therapeutic Uses,” RL Veech, BChance, YKashiwaya, HA Lardy,and GF Cahill, Jr., IUBMB Life, 51: 241–247, 2001

  21. AC-1202 -- MCT Oil for AD Samuel Henderson, Ph.D. files first patent application for use of MCT oil to treat Alzheimer’s disease in 2000: • Insight: Mild ketosis produced by conversion of medium chain fatty acids to ketones in liver may be adequate to produce cognitive improvement in insulin resistant Alzheimer’s brain

  22. Medium Chain Triglycerides Converted to Ketones in Liver

  23. Medium Chain FAs also alternative fuel? • Medium chain fatty acids cross the blood brain barrier • MCFA feeding of lab rodents is associated with a substantial increase in mitochondrial oxidative capacity, which is sufficient to prevent lipid accumulation in this tissue. • MCFAs are oxidized in mitochondria of neurons and contribute to production of ATP (personal communication Dr. Henri Brunengraber). Turner N, K Hariharan, J TidAng, et al. “Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species dependent: potent tissue-specific effects of medium-chain fatty acids.” Diabetes Vol 48 (2009): 2547–2554.

  24. AC-1202 Phase 2a Study - 2004 • 20 persons with mild to moderate AD given single dose tricaprylic acid (40 gm) vs. placebo on another occasion • On average, in nine ApoE4- persons ADAS-Cog improved by average of 6 points (of 75)and improved Paragraph Recall scores 90 minutes after just one dose; ApoE4+ as group did not improve; some individuals did improve. • β OHB levels increased to about 0.5 mmol/L Reger MA, ST Henderson, et. al.“Effects of b-Hydroxybutyrate on cognition in memory-impaired adults,”, Neurobiology of Aging, 2004,Vol. 25, 311-314

  25. AC-1202 Phase 2b Study 2008 • 152 patients with mild to moderate AD received AC-1202 (containing 20 g MCT) or placebo for 90 days in a double-blind, randomized design • Mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant • ApoE4- patients taking AC-1202 differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 and even more significant in dosage compliant patients. Samuel T Henderson*, Janet L Vogel, Linda J Barr, Fiona Garvin, Julie J Jones and Lauren C Costantini. “Study of the ketogenic agent AC-1202 in mild to Moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial,” Nutrition and Metabolism 2009 6(31): 1-25

  26. AC-1202 Phase 2 trials • Similar results in Phase 2 trials in Age-Related Memory Impairment and in Elderly Dogs • Main adverse effect – diarrhea • Approved by FDA as “medical food” and marketed as prescription Axonain spring 2009

  27. May 2008 - 58 years old • Former accountant: can’t use computer , calculator , do simple math • Unable to read due to visual disturbance for 1 ½ years • Problems with word finding and spelling simple words • Doesn’t recognize certain relatives • Slow gait, unable to run • Jaw tremor and intention tremor • Distractible, takes things apart • Personality/sense of humor fading Steve Early Onset Alzheimer’s disease First symptoms 2001 ApoE4+

  28. 12 DAYS BEFORE INTERVENTION • May 9, 2008 • Steve screened for bapineuzimab clinical trial in Tampa, Florida • Met criteria, except scores 12 of 30 on MMSE (Study required score of 16) • Scheduled appointment for May 21, 2008 to try again

  29. 1 DAY BEFORE COCONUT OIL INTERVENTION • May 20, 2008 • Steve screens for Eli Lilly clinical trial in St. Petersburg, FL • Scored only 14 of 30 on MMSE, needed 16 to qualify for study • Clock test– consistent with moderately severe Alzheimer’s

  30. 1st DAY OF COCONUT OIL INTERVENTION • May 21, 2008 - Steve receives 35 grams coconut oil with breakfast = 20 grams medium chain fatty acids (AC-1202 dose) • Screened at Byrd Center for bapineuzimab clinical trial: • Scored18 of 30 onMMSE • Qualified for study

  31. 1 Day Before Starting Coconut Oil

  32. 14 Days After Starting Coconut Oil

  33. 37 Days After Starting Coconut Oil

  34. Steve’s Clocks DAY BEFORE COCONUT OIL 14 DAYS ON COCONUT OIL 37 DAYS ON COCONUT OIL

  35. First Days after Coconut Oil Intervention • Begins daily consumption of coconut oil • Measured dose at breakfast, cooking and other coconut containing foods for lunch and dinner • More alert - Personality and sense of humor resurface • Steve says the “light switch came back on” and the “fog lifted” • Facial tremor no longer apparent • Intention tremor less apparent

  36. Between 0 - 2 months after Intervention • Visual disturbance resolves • Normalization of gait – able to run again • Completes household and gardening tasks with minimal to no supervision and with less distraction • His ability to initiate and continue a course of conversation improves • Recognizes family members that he couldn’t recall one year earlier • Family says he no longer looks lost, conversation makes sense

  37. DAY 51 – Levels after 35 Grams Coconut Oil with Breakfast and with Dinner

  38. DAY 64 - Levels after 20 Grams Medium Chain Triglyceride Oil (C:8)

  39. ADAS-Cog and ADLs • On placebo for first 12 to 14 months of semagacestat trial • Cognitive testing nearly one year after starting MCFAs: • ADAS-Cog improved by 6 points on a 75 point scale from July 23, 2008 to May 9, 2009. Patients on place • Activities of Daily Living score improved by 14 points on a 78 point scale during that same interval.

  40. Stable MRI at 2 Years • 2004: “Normal” MRI • 2008: “Diffuse involutional change of the frontal and parietal lobes and moderate left-sided and severe right-sided amygdala and hippocampal atrophy with no ischemic change, which would support a clinical diagnosis of Alzheimer’s Disease • April 28, 2010 nearly two years after starting MCFAs: • “Stable MRI brain in comparison to prior examination dated 6/16/2008.”

  41. Ketone esters arein development at NIH and University of South Florida KETONE LEVELS: Coconut Oil/MCT Oil 0.3 - 0.5 mmol/l Exercise 0.3 - 0.5 mmol/l Starvation 2-5 mmol/l Classic Ketogenic Diet 2-5 mmol/l Ketone Esters* 2-5 mmol/l** Diabetic Ketoacidosis 25 mmol/l **Beta-hydroxybutyrate ester had no adverse effects in human toxicity testing. FDA: Generally Regarded as Safe.

  42. Ketone Ester at NIH In Alzheimer mouse model: • Reduced plaque • Reduced tangle • Improved memory and learning Kashiwaya Y, Bergman C, Lee J-H, et al. “A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease.” Neurobiology of Aging (Online 2012)

  43. Ketone Effects • Presence of ketone in circulation, even at low levels increases cerebral blood flow by as much as 39% • Ketones used within mitochondria to drive the chain reaction that produces ATP • Reduces generation of free radicals and at same time increases the scavengers of free radicals linked to the NADP system, such as glutathione. • Activates anti-inflammatory mechanisms

  44. Ketone Effects • Treat diseases involving free radical damage such as occurs in coronary reperfusion, diabetic angiopathy, diabetic nephropathy, inflammatory bowel disease, pancreatitis • Suppress cerebral edema and reduce extent of cerebral infarction in brain injury

  45. Byrd Alzheimer’s Institute

  46. Oxygen Toxicity • Alzheimer’s • Epilepsy • ALS • Cancer • Wound Healing Studying ketogenic diets and ketone esters in:

  47. Diseases With Decreased Glucose Uptake into Brain/Nerve Cells • Alzheimer’s disease • Parkinson’s disease • Multiple sclerosis • Huntington’s chorea • ALS/Lou Gehrig’s disease • Duchenne muscular dystrophy • Some forms of autism • Down’s syndrome –develop Alzheimer’s in middle age • Acute brain injury, accompanied by lack of oxygen • Type I and Type II diabetes

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