Development of Alzheimer s Disease: Ketones to Help Rescue a Brain Running Out of Fuel?

Transcription

1 Development of Alzheimer s Disease: Ketones to Help Rescue a Brain Running Out of Fuel? Christian-Alexandre CASTELLANO, PhD Research Center on Aging, CIUSSS de l Estrie CHUS Université de Sherbrooke QC, Canada

2 Disclosures Some of the supplements used in our studies were provided freely by: Abitec Vitaflo Nestlé Ultragenyx Bulletproof Nisshin Oillio

3 Our research group Dr Stephen Cunnane s group: Mélanie Fortier, Valérie St-Pierre, Maggie Roy, Camille Vandenberghe, Marie-Christine Morin, Louise-Andrée Lambert, Etienne Croteau, Michaël Bernier, Alexandre Courchesne-Loyer, C. Alexandre Castellano. Our lab in Sherbrooke (Québec, Canada)

4 Learning Outcomes Define neurocognitive disorders such as Alzheimer's disease. Describe the brain energy problem in the development of Alzheimer's disease. Identify the role of ketones as an alternative fuel to help the starving brain.

5 The concept that drives our research Brain Energy Metabolism Neuronal function Alzheimer s disease

6 The clinical continuum of Alzheimer s disease

7 Alzheimer s disease: facts and figures 1911, Dr Alois Alzheimer presented the description of a patient with presenile dementia that experienced memory loss, paranoia, and psychological changes. The autopsy revealed the presence of presenile plaques (Amyloïd pathology) and neurofibrillary neurodegeneration (Tau pathology) in the brain. NEURON

8 Alzheimer s disease: facts and figures Alzheimer's disease is the most common cause of dementia. Other common types: vascular dementia, frontotemporal dementia, and Lewy body dementia. Dementia = loss of mental ability associated with gradual death of brain cells. (neurogeneration)

9 Alzheimer s disease: facts and figures Estimated number of people living with dementia Source: World Alzheimer Report 2015

10 Alzheimer s disease: facts and figures Estimated prevalence of dementia in Canada Source: CCDSS Public Health Agency of Canada

11 Alzheimer s disease: facts and figures No cure for Alzheimer's disease yet! Several prescription drugs to treat the symptoms of the disease: Cholinesterase inhibitors such as Aricept (donepezil, 1996), Exelon (rivastigmine, 2000), Razadyne (galantamine, 2001). Namenda (memantine, 2003), an N-methyl D-aspartate (NMDA) antagonist. Images IRM -

12 Alzheimer s disease: facts and figures 24 new drugs therapy in phase III clinical trials Cummings et al. Alzheimer's & Dementia, 2016 Images IRM -

13 Alzheimer s disease: facts and figures Types of Alzheimer s disease Familial Alzheimer s disease ( 1%): happens in people age between 30 to 50. Autosomal dominantly inherited genetic mutations on chromosomes 21, 14, and 1. Early-onset Alzheimer's (up to 9%): happens in people age between 40 to 60. Typically shows a strong inheritance pattern; may progress faster and more aggressively. FAD Tau pathology Late-onset Alzheimer's (90%): Sporadic form that happens to people age 65 and older. LOAD Source: Tammie Benzinger (University of Washington)

14 Alzheimer s disease: origin(s) Sporadic Alzheimer s disease (90% of the cases) would be due to a complex combination of genes, environment, and lifestyle. Risk factors: Age, Familial history / genetics (apolipoprotein E4), Low education, High blood pressure, Type II Diabetes, High cholesterol, Obesity and lack of physical activity, Alcohol / Smoking, Depression, Head injuries.

15 Alzheimer s disease: diagnosis The diagnosis of Alzheimer's disease is more a diagnosis of exclusion: untreated sleep disorders (sleep apnea), Possible symptoms depression, alcohol and drug abuse, overuse of prescribed medications, low vitamin B12, folate, thyroid, and vitamin D, neurological diseases (brain tumour, subdural hematoma, seizure disorder)

16 Alzheimer s disease: diagnosis Neuropsychological tests Exclusion criteria Neuroimaging Biomarkers Alzheimer s diagnostic

17 Alzheimer s disease: diagnosis Cognitive tests (screening) Mini-mental state exam (MMSE; score on 30 points)

18 Alzheimer s disease: diagnosis Cognitive tests (screening) Mini-mental state exam (MMSE; score on 30 points) Mini-cog (Word list recall + the clock-drawing test) WORD LIST CLOCK DRAWING I want you to draw a clock for me. First, put in all of the numbers where they go and set the hands to 10 past 11

19 Alzheimer s disease: diagnosis NINCDS-ADRDA Alzheimer's Criteria (1984)? dementia Alzheimer cognitive decline 2 SD Normal cognitive changes Normal aging cognitive decline = ± 1SD

20 Alzheimer s disease: diagnosis NIA-AA criteria (Alzheimer s association, 2011) Normal aging Cognitive function Mild cognitive disorder (MCI) The clinical continuum of Alzheimer s disease Alzheimer s disease Years

21 Alzheimer s disease: diagnosis DSM-5 criteria (American Psychiatric Association, 2013) AD MCI Older Neurocognitive disorder (NCD) due to Alzheimer s disease Major NCD Mild NCD Alzheimer s disease MCI Cognitive Decline 2-3 SD Interfere with independence (impaired activities of daily living) Cognitive Decline 1 2 SD NO interference with independence (intact activities of daily living)

22 Alzheimer s disease: diagnosis Neuropsychological tests Exclusion criteria Neuroimaging Biomarkers Alzheimer s diagnostic

23 MRI images - Alzheimer s disease: diagnosis Neuropathological and neuronal injury markers (NIA-AA criteria, 2011; IWG-2 criteria, 2014) Atrophy (CT-Scan/X-ray or MRI) Normal aging Alzheimer disease

24 Alzheimer s disease: diagnostic Neuropathological and neuronal injury markers (NIA-AA criteria, 2011; IWG-2 criteria, 2014) Atrophy (CT-Scan or MRI) Glucose hypometabolism (FDG-PET) Normal aging VS. Alzheimer s disease Lower glucose metabolism Frontotemporal dementia Johnson et al, Cold Spring Harb Perspect Med 2012; Nasrallah and Dubroff, Nuclear medicine 2013

25 Alzheimer s disease: diagnosis Neuropathological and neuronal injury markers (NIA-AA criteria, 2011; IWG-2 criteria, 2014) Atrophy (CT-Scan or MRI) Glucose hypometabolism (FDG-PET) β-amyloïd (PET-tracer or CSF) and P-Tau (PET-tracer or CSF) Control Alzheimer Maruyama et al, Neuron, 2013 β-amyloïd Tau deposition

26 OUTLINE The sporadic form of AD i.e. no known cause (after age 60-65) is the most common form of the disease. AD is a multifactorial neurodegenerative disorder involving genetic, environmental and lifestyle causes = syndrome of AD dementia. Principal risk factors for AD: age, APOE genotype and cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking). Brain glucose hypometabolism is a marker of AD.

27 Glucose and ketones: the two brain energy fuels

28 Brain energy requirements 60 to 80% to support communication among neurons and their supporting cells. Often 5% associated with momentary demands of the environment. «At rest, but active» (Raichle, Science 2006)

29 Brain & energy fuels = an hybrid vehicle GLUCOSE Principal fuel «our gasoline» Brain KETONES Alternative fuel «our battery for the electric motor»

30 Brain energy metabolism Two different strategies for the two main fuels Cunnane et al Oxford University Press 2017

31 The ketone group Ketones (or Ketone Bodies) = water-soluble compounds acetone acetoacetate beta-hydroxybutyrate

32 Ketone metabolism pathways Liver Brain Brain ATP Cotter et al American Journal of physiology - Heart and Circulatory Physiology 2013 Lipids

33 Brain energy requirements Parameters Infant Adult Brain weight (g) (% body) Fuel consumption (kcal/d) (% body) Belfort and Ehrenkranz, Seminars in Fetal and Neonatal Medicine 2017

34 A brain accustomed to using ketones Mild hyperketonemia is normal in infants (up to 1.0 mm). Ecral and Crawford in Fetal and Neonatal Physiology (Fifth Edition), 2017

35 A brain accustomed to using ketones Mild hyperketonemia is normal in infants (up to 1.0 mm). Human milk rich in fat (MCFA) : source of ketones Morris J. Inherit. Metab. Dis. 2005

36 A brain accustomed to using ketones Mild hyperketonemia is normal in infants (up to 1.0 mm). Human milk rich in fat (MCFA) : source of ketones Ketones supply ~30% of fetal, neonatal brain energy needs (in rats). Lust et al Metabolic Brain Disease 2003

37 A brain accustomed to using ketones Mild hyperketonemia is normal in infants (up to 1.0 mm). Human milk rich in fat (MCFA) : source of ketones Ketones supply ~30% of fetal, neonatal brain energy needs (in rats) Nehlig Epilepsy research 1999

38 A brain accustomed to using ketones 2-3 times more rapid brain ketone uptake in newborn and infants than in adults. Outflow transport Clearance Bougneres, J. Clin. Invest. 1985

39 A brain accustomed to using ketones 2-3 times more rapid brain ketone uptake in newborn and infants than in adults. Ketones supply up to 90% of the carbon to make brain cholesterol (Cunnane, 2003). Koper et al Biochimica et Biophysics Acta 1981

40 OUTLINE The brain is our most energy-consuming organ which makes it vulnerable to energy starvation. Fat-derived ketones (acetoacetate and β-hydroxybutyrate) are the major alternative brain fuel when glucose supply is low. Ketones extraction by neonatal brain is higher than the adult brain ; ketones are important in neuronal development. Ketones are the brain s preferred fuel (the PUSH-PULL strategy)

41 Brain energy problems in Alzheimer s disease and the potential benefice of stimulating ketones

42 Brain glucose problems in MCI and AD Lower brain glucose uptake MCI AD Mosconi et al Eur J Nucl Med Mol Imaging 2005 Croteau et al. Exp. Gerontol. (2017)

43 Brain glucose problems in family history of AD Lower brain glucose uptake versus no family history of AD: maternal paternal both parents Mosconi et al, Neurology, 2009

44 Brain glucose problems in APOE4 carriers Reiman et al, PNAS 2004

45 Brain glucose problems in prediabetics Baker et al, Arch Neurol 2011

46 UTA 565 La recherche au service des aînés 7 octobre 2015 The Hallmarks of Alzheimer's disease Biomarkers abnormality in the AD continum Alzheimer Alzheimer Bateman et al, New England Journal of Medicine 2012

47 Bypassing brain glucose problem in AD 1) Is the brain s capacity to use ketones preserved? 2) How to provide ketones to the brain?

48 Evaluation of brain energy metabolism in vivo Multimodal imaging protocol Structural imaging Functional imaging Ketones Glucose

49 Preservation of brain ketone capacity in AD Croteau et al. Exp. Gerontol. (2017)

50 Stimulation of ketogenesis

51 Stimulation of ketogenesis Short and long-term fasting (in human) Adapted from Owen et al Journal of Clinical Investigation 1967

52 Stimulation of ketogenesis Short and long-term fasting (in human) Cunnane et al. Frontiers Molec. Neurosci 2016

53 Stimulation of ketogenesis Caloric restriction by 40% (in rats) Blood ketones Brain β-hydroxybutyrate Lin et al Neurobiology of Aging 2015

54 Stimulation of ketogenesis Ketogenic diet on biomarkers of CVD risk Ketogenic group (n = 12) Control group (n = 8) Wk 0 Wk 6 %Δ 2 Wk 0 Wk 6 %Δ TC, mmol/l 4.27 ± ± % 4.24 ± ± % TAG, mmol/l 1.09 ± 0.5 a 0.73 ± 0.3 b 33.0% 1.14 ± 0.3 a 1.08 ± 0.7 a 5.3% HDL-C, mmol/l 1.22 ± ± % 1.16 ± ± % LDL-C, mmol/l 2.87 ± ± % 2.89 ± ± % Insulin, pmol/l 23.7 ± 16.3 a 15.6 ± 8.9 b 34.2% 21.5 ± 6.7 a 24.3 ± 9.9 a 13.0% Glucose, mmol/l 5.00 ± ± % 5.00 ± ± % Means in a row with different superscripts differ (P 0.05) TC, total cholesterol; TAG, triacylglycerol Sharman et al Journal of Nutrition 2002

55 Stimulation of ketogenesis All versions of the ketogenic diet: Restrict carbohydrate intake Increase fat intake Only under medical supervision Vitamin and mineral supplements are necessary Diet Classical ketogenic diet (KD) Medium Chain Triglyceride KD Modified Atkins Diet (MAD) Low Glycaemic Index Treatment (LGTI) Design 3-4 (fat) to 1 (non-fat) ratio 30 to 60% fats are MCT usually limited to g of carbohydrate/day (no fibre) Glycemic index of food ; usually 40-60g of carbohydrate/day (incl. fibre)

56 Stimulation of ketogenesis Ketogenic diet some examples

57 Stimulation of ketogenesis Ketogenic diet (in animal model) Fasting (48h) KD diet (2 weeks) Control Diet KD = Fat to non-fat (protein and carbohydrates) ratio of 3.5:1 Pifferi et al. Nutritional Neuroscience 2011

58 Stimulation of ketogenesis Ketogenic diet (in young adults, N=10) Fat to non-fat (protein and carbohydrates) ratio of 4:1 Courchesne-Loyer et al., J Cerebral Blood Flow Metabolism, 2016

59 Stimulation of ketogenesis Ketogenic diet (in MCI; N=10) Low-fat diet 6-weeks Global 11 C-acetoacetate uptake High-fat diet 6-weeks PRE POST Global 11 C-acetoacetate uptake Change in biomarkers in CSF (Total tau - Aβ42) Adapted from Craft et al Alzheimers & Dementia 2016

60 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms.

61 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms (in children). AcAc (mm) B-OHB (mm) Baseline (N=145) 12-month KD diet MCT diet KD diet MCT diet 0.04 ± ± ± 0.69 a 0.71 ± 0.48 b 0.08 ± ± ± ± 1.69 a 3.37 ± 2.81 a Ketogenic diet (KD): 4:1 ratio a, b p < 0.05 Medium Chain Triglyceride diet (MCT): up to 60% of energy and carbohydrate at 15% Adapted from Neel et al Epilepsia 2008

62 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms (in AD) The clock test Day 0 Day 14 Day 37 MMSE = 14/30 MMSE = 17/30 (Mix Coconut oil + MCT tablespoon) x 3/day What if there was a cure for Alzheimer s and no one knew? A case study by Newport. July 22, 2008

63 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms (in AD). AC1202 (N=65) Placebo (N=55) Improvement *P < 0.05 * * 45 d 90 d Participants with AD 20 g/d of MCT (C8) for 90 days Decline Adapted from Henderson et al, BMC Medical Genetics 2011

64 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms (in adults) a, b, c p<0.05 b c a a a CTL Coco C10 C8/C10 C8 Vandenberghe et al. Curr Dev Nutr 2017

65 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms (in AD). Baseline 1-month CMRacac CMRacac Participants with AD (N=9) 30 g/d of MCT (60% C8 / 40% C10) for 1-month Cunnane et al, in progress

66 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms (in MCI). Participants with MCI 30 g/d of MCT vs. Placebo for 6-month Cunnane et al, in progress

67 Stimulation of ketogenesis Medium chain fatty acids with 6 12 carbon atoms (in MCI). BVMTR (Memory) Verbal fluency (Executive function) Participants with MCI 30 g/d of MCT vs. Placebo for 6-month Cunnane et al, in progress

68 Stimulation of ketogenesis «Exogenous Ketones» Ketone Salts Ketone Esters β-hydroxybutyrate salt D-β-hydroxybutyrate ester

69 Stimulation of ketogenesis Ketone Esters D-β-hydroxybutyrate ester Case study report (participant with AD): «After 6-8 weeks of taking 28.7g KE thrice daily,. improvement in memory retrieval,. able to perform more complex tasks». Newport et al, Alzheimer Dementia 2015

70 Stimulation of ketogenesis Aerobic exercise (in young adults, N=7) Féry et Belasse Am J Physiol. 1983

71 Stimulation of ketogenesis Aerobic exercise (in AD) Participants with AD (N=10) up to 40 min 3 times a week for 3 months Acetoacetate (blood) Acetoacetate (brain) CMRacac K acac Castellano et al JAD 2017

72 Stimulation of ketogenesis Aerobic exercise (in AD) Castellano et al JAD 2017

73 Ketones as a neurotherapeutics Ketogenic intervention is the treatment of choice in: Refractory childhood epilepsy; over the last 90 years Brain GLUT-1 deficiency (Pascual et al, 2014; Mochel et al. 2015) Side effects of insulin-induced hypoglycemia in type 1 diabetics (Page et al, 2009)

74 Ketones as a neurotherapeutics Under investigation: Huntington s disease (Mochel et al. Neurology. 2015) Parkinson s disease (Vanitallie et al. Neurology. 2015) Brain cancer (Woolf et al. Front Mol Neurosci. 2016)

75 IN SUMMARY A brain running out of gas may increase the risk of neuronal dysfunction and the risk of Alzheimer s disease. Ketogenic interventions, such as providing MCT (MCFA with 8-10 carbons), could be an easy and effective strategy to reduce the brain energy gap and delay cognitive decline in person at risk to develop Alzheimer s disease or early in the disease. Combining MCFA supplementation with aerobic exercise warrants further research, especially in the context of prevention. LaFerrari, mild hybrid car (963 hp)

76 Acknowledgements Collaborators: Francis Langlois (Memory Clinic); Guy Lacombe, Christian Bocti, Tamas Fülöp, Martin Lepage, Kevin Whittingstall and Maxime Descoteaux (Sherbrooke University); Carol Hudon (Laval University); Serge Gauthier (McGill University), Eric Reiman (Banner Alzheimer's Institute), Suzanne Craft (Wake Forest University); Russell Swerdlow (University of Kansas),. Funding: Alzheimer Association USA, Sojecci II, CFI, CRC, NSERC, CIHR, Pfizer-FRQS, FRQS, CdRV, Mitacs, Fondation Vitae, University of Sherbrooke Research Chair.