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    Schematic depiction of the generation of ATP from glucose or ketones. Glucose enters a cell and progresses through glycolysis to form pyruvate, which is converted to acetyl coenzyme A (Acetyl CoA) in the mitochondria and then enters the tricarboxylic acid (Krebs) cycle. The Krebs cycle produces ATP through oxidative phosphorylation. When glycolysis fails or there is a lack of glucose, there is no pyruvate to drive the subsequent energy-producing processes. In contrast, β-hydroxybutyrate (β-HB) diffuses into the mitochondria and is converted to acetoacetate, which can enter the Krebs cycle. The energy ultimately gained from ketones metabolized through the Krebs cycle and oxidative phosphorylation is identical to that produced by glucose metabolized through the Krebs cycle, which allows ketones to bypass a disrupted glycolysis process.

  • 1. Cummings BJ, Head E, Ruehl W, et al. The canine as an animal model of human aging and dementia. Neurobiol Aging 1996;17:259268.

  • 2. Milgram NW. Cognitive experience and its effect on age-dependent cognitive decline in Beagle dogs. Neurochem Res 2003;28:16771682.

    • Search Google Scholar
    • Export Citation
  • 3. Head E. A canine model of human aging and Alzheimer's disease. Biochim Biophys Act 2013;1832:13841389.

  • 4. Schütt T, Helboe L, Pedersen L, et al. Dogs with cognitive dysfunction syndrome as a spontaneous model for early Alzheimer's disease: a translational study of neuropathological and inflammatory markers. J Alzheimers Dis 2016;52:433449.

    • Search Google Scholar
    • Export Citation
  • 5. Youssef SA, Capucchio MT, Rofina JE, et al. Pathology of the aging brain in domestic and laboratory animals, and animal models of human neurodegenerative diseases. Vet Pathol 2016;53:327348.

    • Search Google Scholar
    • Export Citation
  • 6. Chapagain D, Virányi Z, Huber L, et al. Effect of age and dietary intervention on discrimination learning in pet dogs. Front Psychol 2018;9:2217.

    • Search Google Scholar
    • Export Citation
  • 7. Giaccone G, Verga L, Finazzi M, et al. Cerebral preamyloid deposits and congophilic angiopathy in aged dogs. Neurosci Lett 1990;114:178183.

    • Search Google Scholar
    • Export Citation
  • 8. Cummings BJ, Su JH, Cotman CW, et al. β-amyloid accumulation in aged canine brain: a model of early plaque formation in Alzheimer's disease. Neurobiol Aging 1993;14:547560.

    • Search Google Scholar
    • Export Citation
  • 9. Cummings BJ, Su JH, Cotman CW, et al. β-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol Learn Mem 1996;66:1123.

    • Search Google Scholar
    • Export Citation
  • 10. Head E, Callahan H, Muggenburg BA, et al. Visual-discrimination learning ability and β-amyloid accumulation in the dog. Neurobiol Aging 1998;19:415425.

    • Search Google Scholar
    • Export Citation
  • 11. Su MY, Head E, Brooks WM, et al. Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging. Neurobiol Aging 1998;19:479485.

    • Search Google Scholar
    • Export Citation
  • 12. Borràs D, Ferrer I, Pumarola M. Age-related changes in the brain of the dog. Vet Pathol 1999;36:202211.

  • 13. Dimakopoulos AC, Mayer RJ. Aspects of neurodegeneration in the canine brain. J Nutr 2002;132:1579S1582S.

  • 14. Head E, Moffat K, Das P, et al. β-amyloid deposition and tau phosphorylation in clinically characterized aged cats. Neurobiol Aging 2005;26:749763.

    • Search Google Scholar
    • Export Citation
  • 15. Pugliese M, Gangitano C, Ceccariglia S, et al. Canine cognitive dysfunction and the cerebellum: acetylcholinesterase reduction, neuronal and glial changes. Brain Res 2007;1139:8594.

    • Search Google Scholar
    • Export Citation
  • 16. Head E, Rofina J, Zicker S. Oxidative stress, aging, and central nervous system disease in the canine model of human brain aging. Vet Clin North Am Small Anim Pract 2008;38:167178.

    • Search Google Scholar
    • Export Citation
  • 17. Head E. Neurobiology of the aging dog. Age (Dordr) 2011;33:485496.

  • 18. Yu CH, Song GS, Yhee JY, et al. Histopathological and immunohistochemical comparison of the brain of human patients with Alzheimer's disease and the brain of aged dogs with cognitive dysfunction. J Comp Pathol 2011;145:4558.

    • Search Google Scholar
    • Export Citation
  • 19. Chambers JK, Uchida K, Nakayama H. White matter myelin loss in the brains of aged dogs. Exp Gerontol 2012;47:263269.

  • 20. Dowling A, Head E. Antioxidants in the canine model of human aging. Biochim Biophys Acta Mol Basis Dis 2012;1822:685689.

  • 21. Papaioannou N. Principles of age-related changes in the canine and feline brain. Acta Vet (Beogr) 2014;64:19.

  • 22. Vite CH, Head E. Aging in the canine and feline brain. Vet Clin North Am Small Anim Pract 2014;44:11131129.

  • 23. Romanucci M, Della Salda L. Oxidative stress and protein quality control systems in the aged canine brain as a model for human neurodegenerative disorders. Oxid Med Cell Longev 2015:2015:940131.

    • Search Google Scholar
    • Export Citation
  • 24. Smolek T, Madari A, Farbakova J, et al. Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. J Comp Neurol 2016;524:874895.

    • Search Google Scholar
    • Export Citation
  • 25. Cunnane S, Nugent S, Roy M, et al. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition 2011;27:320.

  • 26. VanItallie TB, Nufert TH. Ketones: metabolism's ugly duckling. Nutr Rev 2003;61:327341.

  • 27. Mergenthaler P, Lindauer U, Dienel G, et al. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 2013;36:587597.

    • Search Google Scholar
    • Export Citation
  • 28. Grimm A, Friedland K, Eckert A. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease. Biogerontology 2016;17:281296.

    • Search Google Scholar
    • Export Citation
  • 29. Ivanisevic J, Stauch K, Petrasheck M, et al. Metabolic drift in the aging brain. Aging 2016;8:10001020.

  • 30. Yin F, Sancheti H, Patil I, et al. Energy metabolism and inflammation in the brain aging and Alzheimer's disease. Free Radic Biol Med 2016;100:108122.

    • Search Google Scholar
    • Export Citation
  • 31. London ED, Ohata M, Takei H, et al. Regional cerebral metabolic rate for glucose in Beagle dogs of different ages. Neurobiol Aging 1983;4:121126.

    • Search Google Scholar
    • Export Citation
  • 32. Head E, Liu J, Hagen TM, et al. Oxidative damage increases with age in a canine model of human brain aging. J Neurochem 2002;82:375381.

    • Search Google Scholar
    • Export Citation
  • 33. Nugent S, Tremblay S, Chen K, et al. Brain glucose and acetoacetate metabolism: a comparison of young and older adults. Neurobiol Aging 2014;35:13861395.

    • Search Google Scholar
    • Export Citation
  • 34. Butterfield DA, Reed T, Newman SF, et al. Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radic Biol Med 2007;43:658677.

    • Search Google Scholar
    • Export Citation
  • 35. Davis PR, Head E. Prevention approaches in a preclinical canine model of Alzheimer's disease: benefits and challenges. Front Pharmacol 2014;5:47.

    • Search Google Scholar
    • Export Citation
  • 36. Landsberg GM, Denenberg S, Araujo J. Cognitive dysfunction in cats: a syndrome we used to dismiss as ‘old age.'. J Feline Med Surg 2010;12:837848.

    • Search Google Scholar
    • Export Citation
  • 37. Landsberg GM, Nichol J, Araujo JA. Cognitive dysfunction syndrome: a disease of canine and feline brain aging. Vet Clin North Am Small Anim Pract 2012;42:749768.

    • Search Google Scholar
    • Export Citation
  • 38. de Rivera C, Boutet I, Zicker S, et al. A novel method for assessing contrast sensitivity in the Beagle dog is sensitive to age and an antioxidant-enriched food. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:379387.

    • Search Google Scholar
    • Export Citation
  • 39. Salvin H, McGreevy P, Sachdev P, et al. Growing old gracefully—behavioral changes associated with “successful aging” in the dog, Canis familiaris. J Vet Behav Clin Appl Res 2011;6:313320.

    • Search Google Scholar
    • Export Citation
  • 40. Fast R, Schütt T, Toft N, et al. An observational study with long-term follow-up of canine cognitive dysfunction: clinical characteristics, survival and risk factors. J Vet Intern Med 2013;27:822829.

    • Search Google Scholar
    • Export Citation
  • 41. Chapagain D, Range F, Huber L, et al. Cognitive aging in dogs. Gerontology 2018;64:165171.

  • 42. Schütt T, Toft N, Berendt M. Cognitive function, progression of age-related behavioral changes, biomarkers and survival in dogs more than 8 years old. J Vet Intern Med 2015;29:15691577.

    • Search Google Scholar
    • Export Citation
  • 43. Madari A, Farbakova J, Katina S, et al. Assessment of severity and progression of canine cognitive dysfunction syndrome using the Canine Dementia Scale (CADES). Appl Anim Behav Sci 2015;171:138145.

    • Search Google Scholar
    • Export Citation
  • 44. Gunn-Moore D, Moffat K, Christie L, et al. Cognitive dysfunction and the neurobiology of ageing in cats. J Small Anim Pract 2007;48:546553.

    • Search Google Scholar
    • Export Citation
  • 45. Gunn-Moore DA. Cognitive dysfunction in cats: clinical assessment and management. Top Companion Anim Med 2011;26:1724.

  • 46. McCune S, Stevenson J, Fretwell L, et al. Ageing does not significantly affect performance in a spatial learning task in the domestic cat (Felis silvestris catus). Appl Anim Behav Sci 2008;112:345356.

    • Search Google Scholar
    • Export Citation
  • 47. Manteca X. Nutrition and behavior in senior dogs. Top Companion Anim Med 2011;26:3336.

  • 48. Karagiannis C, Mills D. Feline cognitive dysfunction syndrome. Vet Focus 2014;24:4247.

  • 49. Nugent S, Courchesne-Loyer A, St-Pierre V, et al. Ketones and brain development: implications for correcting deteriorating brain glucose metabolism during aging. Oilseeds Fats Crops Lipids 2016;23:D110.

    • Search Google Scholar
    • Export Citation
  • 50. Broom GM, Shaw IC, Rucklidge JJ. The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease. Nutrition 2019;60:118121.

    • Search Google Scholar
    • Export Citation
  • 51. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999;15:412426.

    • Search Google Scholar
    • Export Citation
  • 52. Cunnane SC, Courchesne-Loyer A, St-Pierre V, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci 2016;1367:1220.

    • Search Google Scholar
    • Export Citation
  • 53. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer's Disease. Front Mol Neurosci 2016;9:53.

    • Search Google Scholar
    • Export Citation
  • 54. Freemantle E, Vandal M, Tremblay-Mercier J, et al. Omega-3 fatty acids, energy substrates, and brain function during aging. Prostaglandins Leukot Essent Fatty Acids 2006;75:213220.

    • Search Google Scholar
    • Export Citation
  • 55. Hertz L, Chen Y, Waagepetersen H. Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function. J Neurochem 2015;134:720.

    • Search Google Scholar
    • Export Citation
  • 56. Taylor MK, Sullivan DK, Mahnken JD, et al. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease. Alzheimers Dement (N Y) 2017;4:2836.

    • Search Google Scholar
    • Export Citation
  • 57. McDonald TJW, Cervenka MC. Ketogenic diets for adult neurological disorders. Neurotherapeutics 2018;15:10181031.

  • 58. McDonald TJR, Cervenka MC. The expanding role of ketogenic diets in adult neurological disorders. Brain Sci 2018;8:148.

  • 59. Payne NE, Cross JH, Sander JW, et al. The ketogenic and related diets in adolescents and adults—a review. Epilepsia 2011;52:19411948.

    • Search Google Scholar
    • Export Citation
  • 60. Crandall LA. A comparison of ketosis in man and dog. J Biol Chem 1941;138:123128.

  • 61. de Bruijne JJ, Altszuler N, Hampshire J, et al. Fat mobilization and plasma hormone levels in fasted dogs. Metabolism 1981;30:190194.

    • Search Google Scholar
    • Export Citation
  • 62. Puchowicz MA, Smith CL, Bomont C, et al. Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. J Nutr Biochem 2000;11:281287.

    • Search Google Scholar
    • Export Citation
  • 63. Larsen JA, Owens TJ, Fascetti A. Nutritional management of idiopathic epilepsy in dogs. J Am Vet Med Assoc 2014;245:504508.

  • 64. Shah ND, Limketkai BN. The use of medium-chain triglycerides in gastrointestinal disorders. Pract Gastroenterol 2017;41:2028.

  • 65. USDA. USDA Agricultural Research Service. National nutrient database for standard reference release 28. Available at: ndb.nal.usda.gov/ndb/search/list. Accessed May 26, 2019.

    • Search Google Scholar
    • Export Citation
  • 66. Augustin K, Khabbush A, Williams S, et al. Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol 2018;17:8493.

    • Search Google Scholar
    • Export Citation
  • 67. Jensen GL, McGarvey N, Taraszewski R, et al. Lymphatic absorption of enterally fed structured triacylglycerol vs physical mix in a canine model. Am J Clin Nutr 1994;60:518524.

    • Search Google Scholar
    • Export Citation
  • 68. Newton JD, McLoughlin MA. Transport pathways of enterally administered medium-chain triglycerides in dogs, in Proceedings. Iams Nutr Symp, 2000;143152.

    • Search Google Scholar
    • Export Citation
  • 69. Pan Y, Larson B, Araujo JA, et al. Dietary supplementation with medium-chain TAG has long-lasting cognition-enhancing effects in aged dogs. Br J Nutr 2010;103:17461754.

    • Search Google Scholar
    • Export Citation
  • 70. Law TH, Davies ESS, Pan Y, et al. A randomised trial of medium-chain TAG as treatment for dogs with idiopathic epilepsy. Br J Nutr 2015;114:14381447.

    • Search Google Scholar
    • Export Citation
  • 71. Khabbush A, Orford M, Tsai Y, et al. Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: a mechanistic insight into the medium-chain triglyceride ketogenic diet. Epilepsia 2017;58:14231429.

    • Search Google Scholar
    • Export Citation
  • 72. Studzinski CM, MacKay WA, Beckett TL, et al. Induction of ketosis may improve mitochondrial function and decrease steady-state amyloid-β precursor protein (APP) levels in the aged dog. Brain Res 2008;1226:209217.

    • Search Google Scholar
    • Export Citation
  • 73. Paleologou E, Ismayilova N, Kinali M. Use of the ketogenic diet to treat intractable epilepsy in mitochondrial disorders. J Clin Med 2017;6:56.

    • Search Google Scholar
    • Export Citation
  • 74. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 2009;59:293315.

    • Search Google Scholar
    • Export Citation
  • 75. Wang D, Mitchell E. Cognition and synaptic-plasticity related changes in aged rats supplemented with 8- and 10-carbon medium chain triglycerides. PLoS One 2016;11:e0160159.

    • Search Google Scholar
    • Export Citation
  • 76. Taha AY, Henderson ST, Burnham WM. Dietary enrichment with medium chain triglycerides (AC-1203) elevates polyunsaturated fatty acids in the parietal cortex of aged dogs: implications for treating age-related cognitive decline. Neurochem Res 2009;34:16191625.

    • Search Google Scholar
    • Export Citation
  • 77. Hall JA, Jewell DE. Feeding healthy Beagles medium-chain triglycerides, fish oil, and carnitine offsets age-related changes in serum fatty acids and carnitine metabolites. PLoS One 2012;7:e49510.

    • Search Google Scholar
    • Export Citation
  • 78. Kashiwaya Y, Takeshima T, Mori N, et al. D-β-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A 2000;97:54405444.

    • Search Google Scholar
    • Export Citation
  • 79. Duthie SJ, Whalley LJ, Collins AR, et al. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002;75:908913.

    • Search Google Scholar
    • Export Citation
  • 80. Bourre JM. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 1: micronutrients. J Nutr Health Aging 2006;10:377385.

    • Search Google Scholar
    • Export Citation
  • 81. Bourre JM. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 2: macronutrients. J Nutr Health Aging 2006;10:386399.

    • Search Google Scholar
    • Export Citation
  • 82. Selhub J, Troen A, Rosenberg IH. B vitamins and the aging brain. Nutr Rev 2010;68:S112S118.

  • 83. de Jager CA, Oulhag A, Jacoby R, et al. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry 2012;27:592600.

    • Search Google Scholar
    • Export Citation
  • 84. Oulhaj A, Jernerén F, Refsum H, et al. Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in mild cognitive impairment. J Alzheimers Dis 2016;50:547557.

    • Search Google Scholar
    • Export Citation
  • 85. Vauzour D, Camprubi-Robles M, Miguel-Kergoat S, et al. Nutrition for the ageing brain: towards evidence for an optimal diet. Ageing Res Rev 2017;35:222240.

    • Search Google Scholar
    • Export Citation
  • 86. Ostrakhovitch EA, Tabidzadeh S. Homocysteine and age-associated disorders. Ageing Res Rev 2019;49:144164.

  • 87. Solfrizzi V, Agosti P, Lozupone M, et al. Nutritional interventions and cognitive-related outcomes in patients with late-life cognitive disorders: a systematic review. Neurosci Biobehav Rev 2018;95:480498.

    • Search Google Scholar
    • Export Citation
  • 88. Pan Y, Kennedy AD, Jönsson TJ, et al. Cognitive enhancement in old dogs from dietary supplementation with a nutrient blend containing arginine, antioxidants, B vitamins and fish oil. Br J Nutr 2018;119:349358.

    • Search Google Scholar
    • Export Citation
  • 89. Pan Y, Araujo JA, Burrows J, et al. Cognitive enhancement in middle-aged and old cats with dietary supplementation with a nutrient blend containing fish oil, B vitamins, antioxidants and arginine. Br J Nutr 2013;110:4049.

    • Search Google Scholar
    • Export Citation
  • 90. Bauer J. Essential fatty acid metabolism in dogs and cats. Rev Bras Zootec 2008;37:2027.

  • 91. Phillips C. Lifestyle modulators of neuroplasticity: how physical activity, mental engagement, and diet promote cognitive health during aging. Neural Plast 2017;2017:3589271.

    • Search Google Scholar
    • Export Citation
  • 92. Frigerio F, Pasqualini G, Craparotta I, et al. n-3 docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. Brain 2018;141:31303143.

    • Search Google Scholar
    • Export Citation
  • 93. Jiang LH, Shi Y, Wang LS, et al. The influence of orally administered docosahexaenoic acid on cognitive function in aged mice. J Nutr Biochem 2009;20:735741.

    • Search Google Scholar
    • Export Citation
  • 94. Cutuli D. Functional and structural benefits induced by omega-3 polyunsaturated fatty acids during aging. Curr Neuropharmacol 2017;15:534542.

    • Search Google Scholar
    • Export Citation
  • 95. Cederholm T, Salem N, Palmblad J. Omega-3 fatty acids in the prevention of cognitive decline in humans. Adv Nutr 2013;4:672676.

  • 96. Jackson PA, Forster JS, Bell G, et al. DHA supplementation alone or in combination with other nutrients does not modulate cerebral hemodynamics or cognitive function in healthy older adults. Nutrients 2016;8:86.

    • Search Google Scholar
    • Export Citation
  • 97. Weiser MJ, Butt CM, Mohajeri MH. Docosahexaenoic acid and cognition throughout the lifespan. Nutrients 2016;8:99.

  • 98. Hadley KB, Bauer J, Milgram NW. The oil-rich alga Schizochytrium sp. as a dietary source of docosahexaenoic acid improves shape discrimination learning associated with visual processing in a canine model of senescence. Prostaglandins Leukot Essent Fatty Acids 2017;118:1018.

    • Search Google Scholar
    • Export Citation
  • 99. Mazlan M, Hamezah HS, Taridi NM, et al. Effects of aging and tocotrienol-rich fraction supplementation on brain arginine metabolism in rats. Oxid Med Cell Longev 2017;2017:6019796.

    • Search Google Scholar
    • Export Citation
  • 100. Piletz JE, Aricioglu F, Cheng JT, et al. Agmatine: clinical applications after 100 years in translation. Drug Discov Today 2013;18:880893.

    • Search Google Scholar
    • Export Citation
  • 101. Moretti M, Matheus FC, de Oliveira PA, et al. Role of agmatine in neurodegenerative diseases and epilepsy. Front Biosci (Elite Ed) 2014;6:341359.

    • Search Google Scholar
    • Export Citation
  • 102. Cole JT, Mitala CM, Kundu S, et al. Dietary branched chain amino acids ameliorate injury-induced cognitive impairment. Proc Natl Acad Sci U S A 2010;107:366371.

    • Search Google Scholar
    • Export Citation
  • 103. Elkind JA, Lim MM, Johnson BN, et al. Efficacy dosage, and duration of action of branched chain amino acid therapy for traumatic brain injury. Front Neurol 2015;6:73.

    • Search Google Scholar
    • Export Citation
  • 104. Fretwell LK, McCune S, Fone JV, et al. The effect of supplementation with branched-chain amino acids on cognitive function in active dogs. J Nutr 2006;136:2069S2071S.

    • Search Google Scholar
    • Export Citation
  • 105. Snigdha S, de Rivera C, Milgram N, et al. Effect of mitochondrial cofactors and antioxidants supplementation on cognition in the aged canine. Neurobiol Aging 2016;37:171178.

    • Search Google Scholar
    • Export Citation
  • 106. Ueno Y, Koike M, Shimada Y, et al. L-Carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain. J Cereb Blood Flow Metab 2015;35:382391.

    • Search Google Scholar
    • Export Citation
  • 107. Ferreira GC, McKenna MC. L-Carnitine and acetyl-L-carnitine roles and neuroprotection in developing brain. Neurochem Res 2017;42:16611675.

    • Search Google Scholar
    • Export Citation
  • 108. Christie LA, Opii WO, Head E. Strategies for improving cognition with aging: insights from a longitudinal study of antioxidant and behavioral enrichment in canines. Age (Dordr) 2009;31:211220.

    • Search Google Scholar
    • Export Citation
  • 109. Milgram NW, Araujo JA, Hagen TM, et al. Acetyl-L-carnitine and α-lipoic acid supplementation of aged Beagle dogs improves learning in two landmark discrimination tests. FASEB J 2007;21:37563762.

    • Search Google Scholar
    • Export Citation
  • 110. Sechi S, Chiavolelli F, Spissu N, et al. An antioxidant dietary supplement improves brain-derived neurotrophic factor levels in serum of aged dogs: preliminary results. J Vet Med 2015;2015:412501.

    • Search Google Scholar
    • Export Citation
  • 111. Rofina JE, van Ederen AM, Toussaint MJ, et al. Cognitive disturbances in old dogs suffering from the canine counterpart of Alzheimer's disease. Brain Res 2006;1069:216226.

    • Search Google Scholar
    • Export Citation
  • 112. Cotman CW, Head E, Muggenburg BA, et al. Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction. Neurobiol Aging 2002;23:809818.

    • Search Google Scholar
    • Export Citation
  • 113. Milgram NW, Zicker SC, Head E, et al. Dietary enrichment counteracts age-associated cognitive dysfunction in canines. Neurobiol Aging 2002;23:737745.

    • Search Google Scholar
    • Export Citation
  • 114. Zicker SC. Cognitive and behavioral assessment in dogs and pet food market applications. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:455459.

    • Search Google Scholar
    • Export Citation
  • 115. Milgram NW, Siwak CT, Gruet P, et al. Oral administration of adranifil improves discrimination learning in aged Beagle dogs. Pharmacol Biochem Behav 2000;66:301305.

    • Search Google Scholar
    • Export Citation
  • 116. Milgram NW, Head E, Muggenburg B, et al. Landmark discrimination learning in the dog: effects of age, an antioxidant fortified food, and cognitive strategy. Neurosci Biobehav Rev 2002;26:679695.

    • Search Google Scholar
    • Export Citation
  • 117. Milgram NW, Head E, Zicker SC, et al. Long-term treatment with antioxidants and a program of behavioral enrichment reduces age-dependent impairment in discrimination and reversal learning in Beagle dogs. Exp Gerontol 2004;39:753765.

    • Search Google Scholar
    • Export Citation
  • 118. Milgram NW, Head E, Zicker SC, et al. Learning ability in aged Beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging 2005;26:7790.

    • Search Google Scholar
    • Export Citation
  • 119. Christie L-A, Opii WO, Head E, et al. Short-term supplementation with acetyl-L-carnitine and lipoic acid alters plasma protein carbonyl levels but does not improve cognition in aged Beagles. Exp Gerontol 2009;44:752759.

    • Search Google Scholar
    • Export Citation
  • 120. Head E, Nukala VN, Fenoglio KA, et al. Effects of age, dietary, and behavioral enrichment on brain mitochondria in a canine model of human aging. Exp Neurol 2009;220:171176.

    • Search Google Scholar
    • Export Citation
  • 121. Pan Y, Landsberg G, Mougeot I, et al. Efficacy of a therapeutic diet on dogs with signs of cognitive dysfunction syndrome (CDS): a prospective double blinded placebo controlled clinical study. Front Nutr 2018;5:127.

    • Search Google Scholar
    • Export Citation
  • 122. Mecocci P, Tinarelli C, Schulz RJ, et al. Nutraceuticals in cognitive impairment and Alzheimer's disease. Front Pharmacol 2014;5:147.

  • 123. Sharma A, Gerbarg P, Bottiglieri T, et al. S-adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry 2017;78:e656e667.

    • Search Google Scholar
    • Export Citation
  • 124. Gao J, Cahill CM, Huang X, et al. S-adenosyl methionine and transmethylation pathways in neuropsychiatric diseases throughout life. Neurotherapeutics 2018;15:156175.

    • Search Google Scholar
    • Export Citation
  • 125. Madrigano J, Baccarelli A, Mittleman MA, et al. Longitudinal changes in gene-specific DNA methylation. Epigenetics 2012;7:6370.

  • 126. Araujo JA, Faubert ML, Brooks ML, et al. NOVIFIT (NoviSAMe) tablets improve executive function in aged dogs and cats: implications for treatment of cognitive dysfunction syndrome. Int J Appl Res Vet Med 2012;10:9098.

    • Search Google Scholar
    • Export Citation
  • 127. Réme CA, Dramard V, Kern L, et al. Effect of S-adenosylmethionine tablets on the reduction of age-related mental decline in dogs: a double-blinded, placebo-controlled trial. Vet Ther 2008;9:6982.

    • Search Google Scholar
    • Export Citation
  • 128. Milgram NW, Landsberg G, Merrick D, et al. A novel mechanism for cognitive enhancement in aged dogs with the use of a calcium-buffering protein. J Vet Behav 2015;10:217222.

    • Search Google Scholar
    • Export Citation
  • 129. Scott TM, Rasmussen HM, Chen O, et al. Avocado consumption increases macular pigment density in older adults: a randomized, controlled trial. Nutrients 2017;9:919.

    • Search Google Scholar
    • Export Citation
  • 130. Sorrentino V, Romani M, Mouchiroud L, et al. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 2017;552:187193.

    • Search Google Scholar
    • Export Citation
  • 131. Gomez-Pinilla F, Gomez AG. The influence of dietary factors in central nervous system plasticity and injury recovery. PM R 2011;3(suppl 1):S111S116.

    • Search Google Scholar
    • Export Citation
  • 132. Head E, Murphey HL, Dowling ALS, et al. A combination cocktail improves spatial attention in a canine model of human aging and Alzheimer's disease. J Alzheimers Dis 2012;32:10291042.

    • Search Google Scholar
    • Export Citation
  • 133. Heath SE, Barabas S, Craze PG. Nutritional supplementation in cases of canine cognitive dysfunction—a clinical trial. Appl Anim Behav Sci 2007;105:284296.

    • Search Google Scholar
    • Export Citation
  • 134. Araujo JA, Landsberg GM, Milgram NW, et al. Improvement of short-term memory performance in aged Beagles by a nutraceutical supplement containing phosphatidylserine, Gingko biloba, vitamin E, and pyridoxine. Can Vet J 2008;49:379385.

    • Search Google Scholar
    • Export Citation
  • 135. Beata C, Beaumont-Graff E, Diaz C, et al. Effects of alpha-casozepine (Zylkene) versus selegiline hydrochloride (Selgian, Anipryl) on anxiety disorders in dogs. J Vet Behav 2007;2:175183.

    • Search Google Scholar
    • Export Citation
  • 136. Beata C, Beaumont-Graff E, Coll V, et al. Effect of alpha-casozepine (Zylkene) on anxiety in cats. J Vet Behav 2007;2:4046.

  • 137. Orlando JM. Behavioral nutraceuticals and diets. Vet Clin North Am Small Anim Pract 2018;48:473495.

  • 138. Kato M, Miyaji K, Ohtani N, et al. Effects of prescription diet on dealing with stressful situations and performance of anxiety-related behaviors in privately owned anxious dogs. J Vet Behav 2012;7:2126.

    • Search Google Scholar
    • Export Citation
  • 139. Bosch G, Beerda B, Beynan AC, et al. Dietary tryptophan supplementation in privately owned mildly anxious dogs. Appl Anim Behav Sci 2009;121:197205.

    • Search Google Scholar
    • Export Citation
  • 140. DeNapoli JS, Dodman NH, Shuster L. Effect of dietary protein content and tryptophan supplementation on dominance aggression, territorial aggression, and hyperactivity in dogs. J Am Vet Med Assoc 2000;217:504508.

    • Search Google Scholar
    • Export Citation
  • 141. Landsberg G, Milgram B, Mougeot I, et al. Therapeutic effects of an alpha-casozepine and L-tryptophan supplemented diet on fear and anxiety in the cat. J Feline Med Surg 2017;19:594602.

    • Search Google Scholar
    • Export Citation
  • 142. Larson BT, Lawler DF, Spitznagel EL, et al. Improved glucose tolerance with lifetime diet restriction favorably affects disease and survival in dogs. J Nutr 2003;133:28872892.

    • Search Google Scholar
    • Export Citation
  • 143. de J R De-Paula V. Forlenza AS, Forlenza OV. Relevance of gutmicrobiota in cognition, behaviour and Alzheimer's disease. Pharmacol Res 2018;136:2934.

    • Search Google Scholar
    • Export Citation
  • 144. Fülling C, Dinan TG, Cryan JF. Gut microbe to brain signaling: what happens in vagus. Neuron 2019;101:9981002.

  • 145. Bastiaanssen TFS, Cowan CSM, Claesson MJ, et al. Making sense of.the microbiome in psychiatry. Int J Neuropsychopharmacol 2019;22:3752.

    • Search Google Scholar
    • Export Citation
  • 146. Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 2018;23:716724.

    • Search Google Scholar
    • Export Citation
  • 147. McGowan RTS. Oiling the brain or cultivating the gut: impact of diet on anxious behaviors in dogs, in Proceedings. Nestlé Purina Comp Anim Nutr Summit 2016;9197.

    • Search Google Scholar
    • Export Citation

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Nutrition and the aging brain of dogs and cats

Kimberly A. May DVM, MS1 and Dorothy P. Laflamme DVM, PhD1
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  • 1 1From the Purina Institute, Nestle Purina Petcare, 1 Checkerboard Sq, St Louis, MO 63102.

Many nutrients are critical for maintaining brain structure and function, including cognition. A deficiency of some nutrients can lead to compromised brain structure and function, which accelerates brain aging. Additional nutrients may have benefits when provided in quantities greater than those listed in recognized requirements, whereas other nutrients that may be beneficial to cognitive function may not be recognized as essential nutrients. The purpose of the information provided here was to summarize the evidence for beneficial effects of nutrients on brain function and cognition, with an emphasis on the aging brain, and to provide evidence on the dietary management of dogs with cognitive dysfunction syndrome.

Age-related changes in brain structure and metabolism

Aging results in numerous physical, metabolic, and functional changes in the brain that can negatively affect cognition and cause behavioral changes.1–6 Age-associated changes in the brain include regional atrophy of gray and white matter, increases in ventricular volume, irreversible loss of neurons and synapses, reduced neurogenesis, reduced clearance and subsequent accumulation of abnormal proteins (such as β-amyloid), inflammation, oxidative stress, vascular changes (including cerebral amyloid angiopathy), reduction or deterioration of myelin, diminished cholinergic function, and alterations in gene expression.7–24

Energy metabolism in the brain is also altered with age. The brain is a metabolically active organ. In humans, the brain accounts for approximately 20% to 25% of the body's total resting energy metabolism, with most of this energy used to maintain membrane energy potentials necessary for neurotransmission.25 The primary energy source used by the brain is glucose, although ketones can provide an alternate energy source during periods when food is not consumed.26 Because of its high metabolic rate, the brain is particularly vulnerable to and intolerant of disruptions in energy metabolism.27–30 Unfortunately, brain aging is associated with mitochondrial dysfunction and reductions in glucose metabolism.27,29,31–33 The decline in glucose metabolism in the brain contributes to neurodegenerative diseases and appears to be present well in advance of the onset of measurable cognitive decline.25 In dogs, overall brain metabolism and regional metabolic reductions as severe as 25% have been detected by 6 years of age.31 Compromised mitochondrial function reduces energy availability and contributes to increased production of oxygen free radicals and oxidative stress.32 Oxidative stress is also associated with neurodegenerative diseases and cognitive decline.20,34,35

Age-related cognitive dysfunction in dogs and cats

Cognition is defined as the ability to learn, think, solve problems, remember, and communicate. Cats and dogs can age in a manner wherein age-related changes have minimal impact, or they may develop cognitive decline (comparable to mild cognitive impairment in humans) or more severe cognitive dysfunction syndrome (comparable to dementia and Alzheimer disease in humans). Cognitive dysfunction is associated with more severe physical and physiologic changes in the brain and may manifest clinically as disorientation; altered social interactions and sleep-wake cycles; apparent memory and learning deficits, reduced ability to focus, and inappropriate soiling behavior; reductions in activity and interaction with the pet's environment; repetitive behaviors; and increases in anxiety, including separation anxiety and heightened fear of visual or auditory stimuli and new environments.36,37

Even apparently healthy aging animals will have some cognitive impairment as identified by standardized cognitive testing; however, the changes are mild and do not result in altered behaviors or impaired daily function.37–39 Cognitive impairments have been detected in apparently healthy dogs and cats as early as 6 and 7.7 years of age, respectively.37 Cognitive decline typically is progressive, although the rate of progression is highly variable.37,40,41 Investigators of 1 study42 observed that one-third of 21 cognitively normal senior dogs had progression to mild cognitive impairment and approximately one-fourth of 17 mildly impaired dogs had progression to cognitive dysfunction syndrome within a 24-month period. Investigators of another study,43 who used a different assessment scale, observed that of 63 aged dogs, approximately 4 in 10 had progression from normal cognition to mild cognitive impairment within 6 months. In the same study,43 5 of 7 aged dogs evaluated over a 12- to 14-month period had progressed from normal cognition to mild cognitive impairment during that time, and one-half of the dogs that initially had mild impairment had progressed to moderate impairment.

Characterization of cognitive decline and dysfunction in cats lags behind that in dogs, and these conditions appear more challenging to diagnose and may be overlooked in cats.36,44–46 It is estimated that the prevalence of cognitive dysfunction syndrome in cats between 11 and 14 years of age is 28%, and in cats ≥ 15 years old, it increases to > 50%.44,45

Early detection and intervention may provide opportunities to slow the rate of cognitive decline, support the human-animal bond, and address well-being and quality-of-life issues.36,37,47,48 Cognitive decline and cognitive dysfunction syndrome may be managed by targeting the risk factors for cognitive impairment through medical, environmental, and nutritional interventions. Several dietary modifications, including the use of antioxidants, alternative energy sources, vitamins, and omega-3 fatty acids, can impact brain function or cognition in aged pets.

Ketones and MCTs

Glucose cannot be entirely replaced as an energy source for the brain; however, other energy sources can be used to supplement the energy provided by glucose.27,49 Two important alternative sources of energy include ketones and MCFAs derived from MCTs.49,50

Ketone bodies, including acetoacetate and β-hydroxybutyrate, are derived from oxidation of fatty acids. They are able to cross the blood-brain barrier and mitochondrial membrane and can generate ATP via the tricarboxylic acid (Krebs) cycle and oxidative phosphorylation (Figure 1).49,51–53 Glucose metabolism of the brain decreases with age, but ketone metabolism of the brain appears to be unaffected by age.49,50,52,53 Neurons can oxidize ketone bodies at a rate 7 to 9 times the rate for oxidation of glucose, and ketones can provide up to 70% of the brain's energy during prolonged periods when food is not consumed.49,54,55

Figure 1—
Figure 1—

Schematic depiction of the generation of ATP from glucose or ketones. Glucose enters a cell and progresses through glycolysis to form pyruvate, which is converted to acetyl coenzyme A (Acetyl CoA) in the mitochondria and then enters the tricarboxylic acid (Krebs) cycle. The Krebs cycle produces ATP through oxidative phosphorylation. When glycolysis fails or there is a lack of glucose, there is no pyruvate to drive the subsequent energy-producing processes. In contrast, β-hydroxybutyrate (β-HB) diffuses into the mitochondria and is converted to acetoacetate, which can enter the Krebs cycle. The energy ultimately gained from ketones metabolized through the Krebs cycle and oxidative phosphorylation is identical to that produced by glucose metabolized through the Krebs cycle, which allows ketones to bypass a disrupted glycolysis process.

Citation: Journal of the American Veterinary Medical Association 255, 11; 10.2460/javma.255.11.1245

Ketone production is induced in nonfasting humans through the feeding of a ketogenic diet. These diets, which traditionally are extremely high in fat and low in glucose precursors, protein, and carbohydrates (approx 70:20:10, respectively), promote a shift in metabolism to favor ketone production.56 Traditional ketogenic diets have been successfully used in the management of refractory epilepsy in humans and are gaining support for use in the management of a growing number of neurologic disorders, including Alzheimer disease.14,22,37,50,56–58 However, traditional ketogenic diets can induce nutritional deficiencies, and there is often poor compliance to strictly adhere to ketogenic diets because of the severe dietary restrictions.14,56–59 Furthermore, traditional ketogenic diets are not effective in dogs. Dogs do not achieve high ketone concentrations comparable to those in humans consuming traditional ketogenic diets.60–63 In 1 study,a 9 epileptic dogs were fed a traditional ketogenic diet. Although dogs fed the ketogenic diet had significantly higher serum concentrations of β-hydroxybutyrate, compared with concentrations for a control group, there was no difference in seizure frequency between the control group and the group fed the ketogenic diet.

Dietary MCTs can be part of a feeding strategy that results in the endogenous generation of ketones without requiring a high-fat diet. Dietary MCTs are found naturally in milk fat, coconut oil, and palm kernel oil. The MCT oils are concentrated forms of octanoic and decanoic acids, which generally are derived from coconut or palm kernel oil. However, raw coconut oil and palm kernel oil contain only 7% to 12% of these fatty acids, compared with nearly 100% in purified MCT oils.64 Natural coconut oil and palm kernel oil also contain longer-chain fatty acids65 that do not have the same benefits as are seen with octanoic and decanoic acids.

In contrast to long-chain triglycerides, MCTs are rapidly and easily digested without the need for pancreatic lipases or bile acids. The MCTs undergo intraluminal hydrolysis. Most of the MCFAs are absorbed directly through the gastrointestinal wall and are transported via the portal vein to the liver, where they are rapidly oxidized, which results in greater production and release of ketones, compared with results for metabolism of long-chain fatty acids.66 A small but variable amount of MCFAs may be incorporated into chylomicrons and enter the lymphatics, similar to metabolism of long-chain fatty acids. The longer the fatty acid chain (eg, 12 or 10 carbons vs 8 carbons), the more likely that fatty acid is to be found in lymphatic fluids.67,68

The MCT-based ketogenic diets are gaining popularity in human medicine because they provide dietary flexibility (eg, they do not require high amounts of fat) and typically result in better compliance.56,66 Dietary MCTs can stimulate an increase in circulating concentrations of ketones in dogs without limiting dietary protein and carbohydrate intake.24,69,70 In an 8-month study69 of aging dogs without cognitive dysfunction syndrome, feeding an MCT-supplemented diet increased blood β-hydroxybutyrate concentrations and caused enhancements in cognitive function, compared with results for dogs fed a control diet, particularly when the tasks used to test cognitive function of the dogs became more difficult.

It is important to mention that nutritional acetonemia (ketosis) induced by the feeding of traditional or MCT-supplemented ketogenic diets is a physiologic response. In contrast to pathological ketosis, it does not impact blood pH and causes no known adverse effects.51–53

In addition to the ketones generated by the metabolism of MCTs, MCFAs can also be used as an energy source by brain cells. Octanoic acid, an 8-carbon MCFA, is preferentially metabolized for energy and can provide up to 20% of the brain's energy needs.21,66 Both ketones and MCTs (or MCFAs) have cognitive and neuroprotective benefits, including providing an energy source,27,33,49,50,52,53,55,57,58,66,71 reducing oxidative stress,57,58,71–74 enhancing mitochondrial function57,58,71,72,74,75 and mitochondrial biogenesis,57,58,66,73,74 increasing concentrations of omega-3 PUFAs in the brain,72,76,77 reducing concentrations of apoptotic and inflammatory markers,57,58,73,74 reducing concentrations and toxic effects of amyloid-β,50,66,72,78 increasing concentrations of protective neurotrophic factors,74 reducing neuronal hyperactivity and seizure activity,52,53,55,57,58,66,71,73,74 and reducing glutaminergic transmission.66,74 Most of these actions target the physiologic and metabolic changes that lead to neurodegeneration and cognitive decline or dysfunction, which thus provides numerous opportunities for nutritional intervention to prevent or mitigate age-related cognitive impairment. Recently, it has been suggested that at least some of these benefits are mediated by alterations in the gastrointestinal microbiota.57,58

B vitamins

Certain B vitamins, especially thiamine (B1), pyridoxine (B6), folate (B9), and cobalamin (B12), are important for neurodevelopment and cognitive function.79–84 Deficiencies in B vitamins can lead to a high blood concentration of homocysteine,82–84 which is a risk factor for brain atrophy, cognitive impairment, and dementia in humans.79,82,84–86 Long-term provision of B vitamins reduces homocysteine concentrations, oxidative stress, and brain atrophy and improves memory and cognition, compared with results for a placebo.83,87 However, use of B vitamins to slow brain atrophy and cognitive decline provides benefits only in human subjects with high blood concentrations of omega-3 PUFAs.75

The B vitamins are thought to serve roles in dogs and cats that are similar to their roles in humans. However, deficiencies of the B vitamins are uncommon in dogs and cats. The authors are not aware of any studies that found a benefit of increasing the amount of B vitamins beyond the amount typically provided in nutritionally balanced pet foods. However, studies of dogs88 and cats89 revealed cognitive benefits for animals fed a diet supplemented with a blend of B vitamins, omega-3 fatty acids, antioxidants, and other nutrients. Because of the design of the studies, it could not be determined whether the B vitamins specifically contributed to the benefits.

Omega-3 fatty acids

The omega-3 PUFAs, in particular DHA, play critical neuroprotective and anti-inflammatory roles in the brain.85,88,90–92 Neural tissues are rich in DHA, but aging is accompanied by a reduction in DHA content in the brain, which favors neurodegeneration.93,94 Increased intake of long-chain omega-3 PUFAs protects against cognitive decline or improves cognitive function in mice93 and humans.94,95 Interventional studies96,97 conducted to investigate the impact of dietary supplementation with omega-3 PUFAs on cognition in humans have yielded equivocal results because of the study design, dosage, and duration of the study; however, cognitive benefits were typically reported for the use of higher doses and longer durations. The benefits of omega-3 PUFAs in humans may depend on the B vitamin status.84

Studies on the effects of omega-3 PUFAS in dogs and cats are sparse. Investigators of 1 study98 evaluated a marine alga, Schizochytrium sp, as a source of DHA fed to aged Beagles. Over the 25-week study,98 some benefits were observed for visual and variable contrast discrimination learning tests, but there were no enhancements for memory tests. A cocktail of nutrients that included B vitamins and omega-3 PUFAs from fish oil was evaluated in dogs88 and cats.89 The nutrient blends tested in each of those studies resulted in improvements in cognitive function, compared with results for the control groups, but the specific contribution of omega-3 PUFAs to the benefits could not be determined.

Arginine

The amino acid l-arginine serves several roles, including an antioxidant function. It is metabolized in neurons and other cells to form citrulline, which results in the formation of nitric oxide.88,99 Nitric oxide serves as a regulator in a number of physiologic functions, including vascular tone and blood flow, immune responses, neural communication, and expression of antioxidant enzymes. The high metabolic activity of the brain during cognitive tasks results in the use of more oxygen; thus, cognitive activity requires an increase in blood flow, which is primarily mediated by nitric oxide.85

As previously mentioned, l-arginine is metabolized to citrulline. Citrulline derived from l-arginine is a precursor to compounds that support neurogenesis and is also a precursor to the neurotransmitter GABA.99 In addition, l-arginine is also metabolized to form agmatine, a neuromodulator involved in learning and memory processing.99 Agmatine also plays a role in regulating the production of nitric oxide and is thought to provide neuroprotection via multiple mechanisms.99–101

To the authors’ knowledge, no studies have revealed benefits to dogs or cats of increasing the dietary l-arginine content beyond the amount typically provided in nutritionally balanced pet foods. However, studies of dogs88 and cats89 fed a diet supplemented with l-arginine at amounts above the proposed daily requirement in addition to fatty acids, antioxidants, and other nutrients revealed cognitive benefits for animals fed the supplemented diet. However, the degree to which l-arginine or its metabolites specifically contributed to the benefits could not be determined.

Branched-chain amino acids

Branched-chain amino acids may improve hippocampal function and brain networks associated with sleep and wakefulness.102,103 Through their role in de novo synthesis of glutamate, branched-chain amino acids play an intrinsic role in maintaining glutamate and GABA stores in the brain.102 Feeding diets supplemented with branched-chain amino acids (40% valine, 35% leucine, and 25% isoleucine) before and during exercise improves cognitive performance in human athletes.104 In a preliminary study,104 senior dogs that were provided a similar branched-chain amino acid product before (but not during) agility trials made fewer total errors during subsequent trials, which suggested a cognitive benefit.

l-carnitine

One of the functions of l-carnitine is to facilitate transfer of long-chain fatty acids into the mitochondria for β-oxidation, and l-carnitine can enhance mitochondrial function in cardiac and other tissues.105,106 In the brain of adult humans, fatty acids are preferentially incorporated into structural lipids, rather than being oxidized, which potentially limits the value of l-carnitine's transfer facilitation in adults.107 However, l-carnitine also functions as an antioxidant. In rodents subjected to increased amounts of oxidative stress, l-carnitine reduced oxidative injury, enhanced recovery from oxidative stress, and aided cognitive function after recovery.106 Cognitive function improved in aging dogs fed a combination of the mitochondrial cofactors l-carnitine (or its metabolite, acetyl-l-carnitine) and α-lipoic acid, but it did not improve when the components were fed separately.105,108,109

Antioxidants

Oxidative stress is caused by an imbalance between pro-oxidative enzymes (eg, NADPH oxidase, xanthine oxidase, or enzymes in the mitochondrial respiratory chain) and antioxidative enzymes (eg, superoxide dismutase or catalase) and nutrients (eg, vitamins E and C). Antioxidants bind to, prevent the formation of, or capture free electrons (free radicals) on reactive oxygen species.16 The body produces numerous compounds and enzymes that function as antioxidants16,110; however, endogenous antioxidant capacity decreases with age, which results in oxidative stress. Because of its extremely high metabolic rate and relatively low amount of endogenous antioxidants, the brain is particularly susceptible to oxidative stress.34

Brain mitochondrial function becomes less efficient during aging, which results in increases in the production of free radicals and increases in oxidative stress that can accelerate brain aging and neurodegeneration.41 Increased amounts of oxidative stress are correlated with the severity of behavioral changes associated with cognitive dysfunction syndrome.111 Dietary supplementation with antioxidants can enhance cognitive function and slow cognitive decline in several species, including rats100 and dogs.112–114

Combinations of nutrients

As mentioned previously, combinations of nutrients provided benefits that were not apparent for single nutrients. An increasing body of evidence suggests that combinations of nutrients provide more promising results than the use of single nutrients.87

Numerous studies have been conducted to evaluate the effects of antioxidants in combination with a number of additional nutrients. Combinations of antioxidants and mitochondrial cofactors enhance cognitive function in dogs.16,112,114,115

Aged dogs fed a diet containing vitamin E, vitamin C, mitochondrial cofactors α-lipoic acid and L-carnitine, and a mixture of fruits and vegetables made fewer errors on cognitive tests, compared with results for dogs fed a control diet.16,113,114,116 The improvements were substantially enhanced when the diet was coupled with environmental enrichment, which indicated a complementary and synergistic effect of environmental enrichment and antioxidants.2,108,114,116–119 A subsequent clinical investigation114,120 of the effects of antioxidants combined with environmental enrichment revealed improvements in age-related behavioral changes in pet dogs as well as improvements in mitochondrial function. Results of an investigation of the effects of α-lipoic acid and acetyl-L-carnitine suggested that these individual components may have improved long-term memory but did not affect other cognitive measures.105,119

Aged dogs88 and cats89 fed a combination of fish oil, antioxidants, arginine, and B vitamins had significantly better cognitive function, compared with aged cats and dogs fed a control diet. Dogs with cognitive dysfunction syndrome that were fed a diet with the same combination of fish oil, antioxidants, arginine, and B vitamins but that also contained MCTs had significant improvements in aberrant behaviors associated with cognitive dysfunction syndrome beginning within 30 days after the onset of the dietary intervention.121

A 1-year trial of pet dogs fed a diet supplemented with antioxidants, omega-3 fatty acids, phosphatidylserine, and tryptophan failed to detect an impact on cognition.6 Authors of the study6 suggested that the lack of effect may have been attributable to the simplicity of the test used for evaluation. This argument is consistent with findings of another study88 in which investigators found that enrichment benefits were best observed when more complicated cognitive tests were used.

Nutraceuticals

Nutraceuticals are nutrients and other compounds, usually provided as oral products, that confer medical or health benefits.122 Many nutraceuticals have purported cognitive benefits.

S-adenosylmethionine is a universal methyl group donor that is believed to play important roles in membrane fluidity, receptor function, and neurotransmitter turnover as well as promotion of endogenous antioxidant capacity.123 Reduced amounts of SAMe and DNA methylation have been associated with aging as well as a number of neuropsychiatric disorders in humans,124,125 and dietary supplementation with SAMe may partially mitigate these clinical effects.124 A meta-analysis of human studies yielded preliminary support for the cognitive benefits of SAMe, although further studies were recommended.123 Provision of SAMe to aged Beagles and cats without cognitive dysfunction syndrome significantly improved executive function (including goal-oriented behavior, decision-making, and problem solving) but not memory.126 In dogs with age-related cognitive decline, provision of SAMe improved activity and awareness and decreased the mental impairment score in a double-blinded, placebo-controlled trial.127

Apoaequorin, a calcium-binding protein that originates from jellyfish, is believed to improve age-associated intracellular calcium dysregulation that can lead to neurodegeneration and neuronal cell death.b Human subjects who received the nutraceutical had significant improvement in cognitive tasks, compared with results for those who received a placebo in a double-blinded study.b Apoaequorin improved the performance of aged Beagles for learning and attention tasks, but not memory tasks, and dogs that received 10 mg of apoaequorin performed better on those same tasks than dogs that received selegiline.128

Other substances with putative benefits for cognitive impairment and dysfunction include cysteine and methionine (endogenous antioxidant production), inositol (neurotransmitter cofactor), phosphatidylserine (membrane quality), choline (acetylcholine precursor), avocado oil (antioxidant and preserves mitochondrial function), nicotinamide riboside (nicotinamide adenine dinucleotide precursor and mitochondrial homeostasis), N-acetylcysteine (antioxidant), and Gingko biloba (monamine oxidase inhibitor that can increase serotonin and dopamine concentrations).36,129,130 Polyphenols (eg, resveratrol, curcumin, and flavonoids) are believed to decrease oxidative stress and enhance mitochondrial homeostasis, and they have received attention for their purported cognitive and health benefits.86,122,131 A supplement-type product that contained melatonin and astaxanthin (a marine algae-derived antioxidant) improved selective attention and motor learning in dogs, but it did not improve working memory.c Aged Beagles fed a combination of turmeric, green tea extract, N-acetylcysteine, α-lipoic acid, and black pepper extract made fewer errors on an attention task, but no significant differences for other cognitive tests were detected.35,132

Many nutraceutical products currently available to veterinarians and pet owners include a combination of several ingredients, including antioxidants, minerals, and vitamins. Use of a combination nutraceuticald significantly improved a number of cognitive dysfunction syndrome-associated signs in aged dogs in a multicenter, double-blinded, placebo-controlled clinical trial133; however, the dogs relapsed once administration of the nutraceutical was discontinued. Use of another combination nutraceuticale improved short-term memory and significantly improved behavioral signs in a small sample of dogs with cognitive dysfunction syndrome.134 Administration of a choline-based combination nutraceuticalf lessened confusion and improved appetite in aged cats.36

A number of nutraceuticals can decrease anxious behaviors in dogs and cats, although few studies have been conducted to specifically evaluate their effects in aging pets. α-Casozepine, which is derived from bovine milk casein, is similar in structure to the inhibitory neurotransmitter GABA and exerts benzodiazepine-like anxiolysis without sedative effects.135–137 Use of an α-casozepine nutraceuticalg resulted in improvements in some fearful behaviors of cats.136 However, 3 of the 4 aged (≥ 10 years old) cats in that study136 were assigned to the placebo group, and the 1 aged cat in the treatment group had no improvement. Administration of the same nutraceutical resulted in anxiolysis comparable to that seen after the administration of selegiline to adult dogs.135 However, the oldest dog in that study135 was only 6.5 years old. Other nutraceuticals with reported anxiolytic benefits, but that have not been specifically investigated to determine their effects on cognition and behavior in aged pets, include L-theanine, a tea plant-origin amino acid that reduces excitatory neurotransmission by competing for binding on glutamate receptors, and melatonin, which binds GABA receptors and has purported benefits for disturbances in sleep-wake cycles, fear, and anxiety but that lacks scientific support for its use in pets.137

Dietary supplementation with tryptophan has been investigated to determine its anxiolytic benefits; tryptophan is a precursor for the neurotransmitter serotonin.137,138 Diets supplemented with tryptophan or a combination of tryptophan, beet pulp, salmon oil, soy, lecithin, and green tea increase plasma tryptophan concentrations in dogs but do not cause detectable changes in behavior139; however, dogs in that study may not have been sufficiently anxious to enable detection of noticeable changes. Because other amino acids compete with tryptophan for transport molecules, the ratio of tryptophan to other dietary amino acids may mediate the effects of dietary supplementation with tryptophan.137,140

A diet combining α-casozepine and tryptophan improves some anxiety-related behaviors in adult dogs, but a placebo effect cannot be ruled out.138 Results of a study141 on a similar diet fed to cats suggest that the diet has anxiolytic effects, but it is recommended that more research be conducted to determine those effects.

Caloric restriction and cognition

There is evidence to suggest that caloric restriction without malnutrition has neuroprotective effects, including reduction of oxidative stress, increased production of brain-derived neurotrophic factor, improvements in mitochondrial function and metabolic efficiency, reduction in apoptosis, and improvements in glucose metabolism of the brain.74,85 However, to the authors’ knowledge, cognitive effects of caloric restriction in dogs and cats have not been assessed. Dogs with long-term calorie restriction had enhanced systemic glucose metabolism during aging, but its impact on cognitive function was not evaluated.142 Caloric restriction is a common characteristic of traditional ketogenic diets,75 but studies69,70,72,76,121 have not investigated the effects of caloric restriction in combination with an MCT-based ketogenic diet.

The gut-brain axis and cognition

The gastrointestinal microbiota affects brain function and behavior, and the brain, in turn, influences the microbiota through top-down and bottom-up bidirectional intercommunication.143 Although the mechanisms involved in the gut-brain axis have not been fully elucidated, known mechanisms include microbiota-stimulated release of gastrointestinal peptides and hormones, microbiota-induced cytokine and chemokine release, activation of the immune system, and bidirectional communication via the vagus nerve.144,145

A clear association exists between the microbiota and anxiety, and there is growing support for a role of the microbiota in age-related cognitive decline.145 Tryptophan metabolism plays a central role in microbiota-host interactions. The gastrointestinal microbiota regulates the availability of tryptophan for conversion to serotonin,146 which introduces complexity to the investigation of dietary supplementation with tryptophan to manage anxiety. Certain gastrointestinal bacteria, including Bifidobacterium longum, are associated with anxiolytic effects. Dietary supplementation with a strain of B longum reduced cortisol concentrations, heart rate, and several anxious behaviors in dogs.147 The existence of complex and robust interactions, even interdependence, of the gastrointestinal microbiome and brain has complicated investigations of nutritional interventions in health and disease, but those interactions also provide ample opportunity to influence brain health through nutrition.

Clinical summary

Aging results in changes in brain metabolism, and many risk factors associated with the underlying pathological processes have been identified. Nutritional interventions targeted to address underlying risk factors provide opportunities to slow cognitive decline, mitigate the behavioral signs of cognitive dysfunction, and improve quality of life for senior pets. Although cognitive decline and cognitive dysfunction may occur as pets age, neither should be accepted as simply a consequence of aging. On the basis of the changes that occur in the aging brain and the risk factors associated with accelerated brain aging and neurodegeneration, it is apparent that nutritional support complements appropriate medical treatment and provides opportunities to mitigate behavioral changes seen as a result of neurodegeneration.

Acknowledgments

The authors declare there were no conflicts of interest.

ABBREVIATIONS

DHA

Docosahexaenoic acid

GABA

γ-Aminobutyric acid

MCFA

Medium-chain fatty acid

MCT

Medium-chain triglyceride

PUFA

Polyunsaturated fatty acid

SAMe

S-adenosylmethionine

Footnotes

a.

Patterson EE, Munana KR, Kirk CA, et al. Results of a ketogenic food trial for dogs with idiopathic epilepsy (abstr). J Vet Intern Med 2005; 19:421.

b.

Underwood M, Sivesind P, Gabourie T. Effect of apoaequorin on cognitive function (abstr). J Alzheimers Dementia 2011;7:e65.

c.

Zanghi B, Araujo J, Milgram NW. PM-supplementation with melatonin, zinc, and Haematococcus pluvialis selectively improves attention and motor learning in aged, memory-impaired dogs (abstr). J Vet Intern Med 2014;28:1087.

d.

Aktivait, VetPlus, Lytham St Annes, England.

e.

Senilife, Ceva Animal Health, Lenexa, Kan.

f.

Cholodin, MVP Laboratories Inc, Omaha, Neb.

g.

Zylkene, Vetoquinol, Fort Worth, Tex.

References

  • 1. Cummings BJ, Head E, Ruehl W, et al. The canine as an animal model of human aging and dementia. Neurobiol Aging 1996;17:259268.

  • 2. Milgram NW. Cognitive experience and its effect on age-dependent cognitive decline in Beagle dogs. Neurochem Res 2003;28:16771682.

    • Search Google Scholar
    • Export Citation
  • 3. Head E. A canine model of human aging and Alzheimer's disease. Biochim Biophys Act 2013;1832:13841389.

  • 4. Schütt T, Helboe L, Pedersen L, et al. Dogs with cognitive dysfunction syndrome as a spontaneous model for early Alzheimer's disease: a translational study of neuropathological and inflammatory markers. J Alzheimers Dis 2016;52:433449.

    • Search Google Scholar
    • Export Citation
  • 5. Youssef SA, Capucchio MT, Rofina JE, et al. Pathology of the aging brain in domestic and laboratory animals, and animal models of human neurodegenerative diseases. Vet Pathol 2016;53:327348.

    • Search Google Scholar
    • Export Citation
  • 6. Chapagain D, Virányi Z, Huber L, et al. Effect of age and dietary intervention on discrimination learning in pet dogs. Front Psychol 2018;9:2217.

    • Search Google Scholar
    • Export Citation
  • 7. Giaccone G, Verga L, Finazzi M, et al. Cerebral preamyloid deposits and congophilic angiopathy in aged dogs. Neurosci Lett 1990;114:178183.

    • Search Google Scholar
    • Export Citation
  • 8. Cummings BJ, Su JH, Cotman CW, et al. β-amyloid accumulation in aged canine brain: a model of early plaque formation in Alzheimer's disease. Neurobiol Aging 1993;14:547560.

    • Search Google Scholar
    • Export Citation
  • 9. Cummings BJ, Su JH, Cotman CW, et al. β-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol Learn Mem 1996;66:1123.

    • Search Google Scholar
    • Export Citation
  • 10. Head E, Callahan H, Muggenburg BA, et al. Visual-discrimination learning ability and β-amyloid accumulation in the dog. Neurobiol Aging 1998;19:415425.

    • Search Google Scholar
    • Export Citation
  • 11. Su MY, Head E, Brooks WM, et al. Magnetic resonance imaging of anatomic and vascular characteristics in a canine model of human aging. Neurobiol Aging 1998;19:479485.

    • Search Google Scholar
    • Export Citation
  • 12. Borràs D, Ferrer I, Pumarola M. Age-related changes in the brain of the dog. Vet Pathol 1999;36:202211.

  • 13. Dimakopoulos AC, Mayer RJ. Aspects of neurodegeneration in the canine brain. J Nutr 2002;132:1579S1582S.

  • 14. Head E, Moffat K, Das P, et al. β-amyloid deposition and tau phosphorylation in clinically characterized aged cats. Neurobiol Aging 2005;26:749763.

    • Search Google Scholar
    • Export Citation
  • 15. Pugliese M, Gangitano C, Ceccariglia S, et al. Canine cognitive dysfunction and the cerebellum: acetylcholinesterase reduction, neuronal and glial changes. Brain Res 2007;1139:8594.

    • Search Google Scholar
    • Export Citation
  • 16. Head E, Rofina J, Zicker S. Oxidative stress, aging, and central nervous system disease in the canine model of human brain aging. Vet Clin North Am Small Anim Pract 2008;38:167178.

    • Search Google Scholar
    • Export Citation
  • 17. Head E. Neurobiology of the aging dog. Age (Dordr) 2011;33:485496.

  • 18. Yu CH, Song GS, Yhee JY, et al. Histopathological and immunohistochemical comparison of the brain of human patients with Alzheimer's disease and the brain of aged dogs with cognitive dysfunction. J Comp Pathol 2011;145:4558.

    • Search Google Scholar
    • Export Citation
  • 19. Chambers JK, Uchida K, Nakayama H. White matter myelin loss in the brains of aged dogs. Exp Gerontol 2012;47:263269.

  • 20. Dowling A, Head E. Antioxidants in the canine model of human aging. Biochim Biophys Acta Mol Basis Dis 2012;1822:685689.

  • 21. Papaioannou N. Principles of age-related changes in the canine and feline brain. Acta Vet (Beogr) 2014;64:19.

  • 22. Vite CH, Head E. Aging in the canine and feline brain. Vet Clin North Am Small Anim Pract 2014;44:11131129.

  • 23. Romanucci M, Della Salda L. Oxidative stress and protein quality control systems in the aged canine brain as a model for human neurodegenerative disorders. Oxid Med Cell Longev 2015:2015:940131.

    • Search Google Scholar
    • Export Citation
  • 24. Smolek T, Madari A, Farbakova J, et al. Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment. J Comp Neurol 2016;524:874895.

    • Search Google Scholar
    • Export Citation
  • 25. Cunnane S, Nugent S, Roy M, et al. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition 2011;27:320.

  • 26. VanItallie TB, Nufert TH. Ketones: metabolism's ugly duckling. Nutr Rev 2003;61:327341.

  • 27. Mergenthaler P, Lindauer U, Dienel G, et al. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 2013;36:587597.

    • Search Google Scholar
    • Export Citation
  • 28. Grimm A, Friedland K, Eckert A. Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease. Biogerontology 2016;17:281296.

    • Search Google Scholar
    • Export Citation
  • 29. Ivanisevic J, Stauch K, Petrasheck M, et al. Metabolic drift in the aging brain. Aging 2016;8:10001020.

  • 30. Yin F, Sancheti H, Patil I, et al. Energy metabolism and inflammation in the brain aging and Alzheimer's disease. Free Radic Biol Med 2016;100:108122.

    • Search Google Scholar
    • Export Citation
  • 31. London ED, Ohata M, Takei H, et al. Regional cerebral metabolic rate for glucose in Beagle dogs of different ages. Neurobiol Aging 1983;4:121126.

    • Search Google Scholar
    • Export Citation
  • 32. Head E, Liu J, Hagen TM, et al. Oxidative damage increases with age in a canine model of human brain aging. J Neurochem 2002;82:375381.

    • Search Google Scholar
    • Export Citation
  • 33. Nugent S, Tremblay S, Chen K, et al. Brain glucose and acetoacetate metabolism: a comparison of young and older adults. Neurobiol Aging 2014;35:13861395.

    • Search Google Scholar
    • Export Citation
  • 34. Butterfield DA, Reed T, Newman SF, et al. Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radic Biol Med 2007;43:658677.

    • Search Google Scholar
    • Export Citation
  • 35. Davis PR, Head E. Prevention approaches in a preclinical canine model of Alzheimer's disease: benefits and challenges. Front Pharmacol 2014;5:47.

    • Search Google Scholar
    • Export Citation
  • 36. Landsberg GM, Denenberg S, Araujo J. Cognitive dysfunction in cats: a syndrome we used to dismiss as ‘old age.'. J Feline Med Surg 2010;12:837848.

    • Search Google Scholar
    • Export Citation
  • 37. Landsberg GM, Nichol J, Araujo JA. Cognitive dysfunction syndrome: a disease of canine and feline brain aging. Vet Clin North Am Small Anim Pract 2012;42:749768.

    • Search Google Scholar
    • Export Citation
  • 38. de Rivera C, Boutet I, Zicker S, et al. A novel method for assessing contrast sensitivity in the Beagle dog is sensitive to age and an antioxidant-enriched food. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:379387.

    • Search Google Scholar
    • Export Citation
  • 39. Salvin H, McGreevy P, Sachdev P, et al. Growing old gracefully—behavioral changes associated with “successful aging” in the dog, Canis familiaris. J Vet Behav Clin Appl Res 2011;6:313320.

    • Search Google Scholar
    • Export Citation
  • 40. Fast R, Schütt T, Toft N, et al. An observational study with long-term follow-up of canine cognitive dysfunction: clinical characteristics, survival and risk factors. J Vet Intern Med 2013;27:822829.

    • Search Google Scholar
    • Export Citation
  • 41. Chapagain D, Range F, Huber L, et al. Cognitive aging in dogs. Gerontology 2018;64:165171.

  • 42. Schütt T, Toft N, Berendt M. Cognitive function, progression of age-related behavioral changes, biomarkers and survival in dogs more than 8 years old. J Vet Intern Med 2015;29:15691577.

    • Search Google Scholar
    • Export Citation
  • 43. Madari A, Farbakova J, Katina S, et al. Assessment of severity and progression of canine cognitive dysfunction syndrome using the Canine Dementia Scale (CADES). Appl Anim Behav Sci 2015;171:138145.

    • Search Google Scholar
    • Export Citation
  • 44. Gunn-Moore D, Moffat K, Christie L, et al. Cognitive dysfunction and the neurobiology of ageing in cats. J Small Anim Pract 2007;48:546553.

    • Search Google Scholar
    • Export Citation
  • 45. Gunn-Moore DA. Cognitive dysfunction in cats: clinical assessment and management. Top Companion Anim Med 2011;26:1724.

  • 46. McCune S, Stevenson J, Fretwell L, et al. Ageing does not significantly affect performance in a spatial learning task in the domestic cat (Felis silvestris catus). Appl Anim Behav Sci 2008;112:345356.

    • Search Google Scholar
    • Export Citation
  • 47. Manteca X. Nutrition and behavior in senior dogs. Top Companion Anim Med 2011;26:3336.

  • 48. Karagiannis C, Mills D. Feline cognitive dysfunction syndrome. Vet Focus 2014;24:4247.

  • 49. Nugent S, Courchesne-Loyer A, St-Pierre V, et al. Ketones and brain development: implications for correcting deteriorating brain glucose metabolism during aging. Oilseeds Fats Crops Lipids 2016;23:D110.

    • Search Google Scholar
    • Export Citation
  • 50. Broom GM, Shaw IC, Rucklidge JJ. The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease. Nutrition 2019;60:118121.

    • Search Google Scholar
    • Export Citation
  • 51. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999;15:412426.

    • Search Google Scholar
    • Export Citation
  • 52. Cunnane SC, Courchesne-Loyer A, St-Pierre V, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci 2016;1367:1220.

    • Search Google Scholar
    • Export Citation
  • 53. Cunnane SC, Courchesne-Loyer A, Vandenberghe C, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer's Disease. Front Mol Neurosci 2016;9:53.

    • Search Google Scholar
    • Export Citation
  • 54. Freemantle E, Vandal M, Tremblay-Mercier J, et al. Omega-3 fatty acids, energy substrates, and brain function during aging. Prostaglandins Leukot Essent Fatty Acids 2006;75:213220.

    • Search Google Scholar
    • Export Citation
  • 55. Hertz L, Chen Y, Waagepetersen H. Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function. J Neurochem 2015;134:720.

    • Search Google Scholar
    • Export Citation
  • 56. Taylor MK, Sullivan DK, Mahnken JD, et al. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease. Alzheimers Dement (N Y) 2017;4:2836.

    • Search Google Scholar
    • Export Citation
  • 57. McDonald TJW, Cervenka MC. Ketogenic diets for adult neurological disorders. Neurotherapeutics 2018;15:10181031.

  • 58. McDonald TJR, Cervenka MC. The expanding role of ketogenic diets in adult neurological disorders. Brain Sci 2018;8:148.

  • 59. Payne NE, Cross JH, Sander JW, et al. The ketogenic and related diets in adolescents and adults—a review. Epilepsia 2011;52:19411948.

    • Search Google Scholar
    • Export Citation
  • 60. Crandall LA. A comparison of ketosis in man and dog. J Biol Chem 1941;138:123128.

  • 61. de Bruijne JJ, Altszuler N, Hampshire J, et al. Fat mobilization and plasma hormone levels in fasted dogs. Metabolism 1981;30:190194.

    • Search Google Scholar
    • Export Citation
  • 62. Puchowicz MA, Smith CL, Bomont C, et al. Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. J Nutr Biochem 2000;11:281287.

    • Search Google Scholar
    • Export Citation
  • 63. Larsen JA, Owens TJ, Fascetti A. Nutritional management of idiopathic epilepsy in dogs. J Am Vet Med Assoc 2014;245:504508.

  • 64. Shah ND, Limketkai BN. The use of medium-chain triglycerides in gastrointestinal disorders. Pract Gastroenterol 2017;41:2028.

  • 65. USDA. USDA Agricultural Research Service. National nutrient database for standard reference release 28. Available at: ndb.nal.usda.gov/ndb/search/list. Accessed May 26, 2019.

    • Search Google Scholar
    • Export Citation
  • 66. Augustin K, Khabbush A, Williams S, et al. Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol 2018;17:8493.

    • Search Google Scholar
    • Export Citation
  • 67. Jensen GL, McGarvey N, Taraszewski R, et al. Lymphatic absorption of enterally fed structured triacylglycerol vs physical mix in a canine model. Am J Clin Nutr 1994;60:518524.

    • Search Google Scholar
    • Export Citation
  • 68. Newton JD, McLoughlin MA. Transport pathways of enterally administered medium-chain triglycerides in dogs, in Proceedings. Iams Nutr Symp, 2000;143152.

    • Search Google Scholar
    • Export Citation
  • 69. Pan Y, Larson B, Araujo JA, et al. Dietary supplementation with medium-chain TAG has long-lasting cognition-enhancing effects in aged dogs. Br J Nutr 2010;103:17461754.

    • Search Google Scholar
    • Export Citation
  • 70. Law TH, Davies ESS, Pan Y, et al. A randomised trial of medium-chain TAG as treatment for dogs with idiopathic epilepsy. Br J Nutr 2015;114:14381447.

    • Search Google Scholar
    • Export Citation
  • 71. Khabbush A, Orford M, Tsai Y, et al. Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: a mechanistic insight into the medium-chain triglyceride ketogenic diet. Epilepsia 2017;58:14231429.

    • Search Google Scholar
    • Export Citation
  • 72. Studzinski CM, MacKay WA, Beckett TL, et al. Induction of ketosis may improve mitochondrial function and decrease steady-state amyloid-β precursor protein (APP) levels in the aged dog. Brain Res 2008;1226:209217.

    • Search Google Scholar
    • Export Citation
  • 73. Paleologou E, Ismayilova N, Kinali M. Use of the ketogenic diet to treat intractable epilepsy in mitochondrial disorders. J Clin Med 2017;6:56.

    • Search Google Scholar
    • Export Citation
  • 74. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev 2009;59:293315.

    • Search Google Scholar
    • Export Citation
  • 75. Wang D, Mitchell E. Cognition and synaptic-plasticity related changes in aged rats supplemented with 8- and 10-carbon medium chain triglycerides. PLoS One 2016;11:e0160159.

    • Search Google Scholar
    • Export Citation
  • 76. Taha AY, Henderson ST, Burnham WM. Dietary enrichment with medium chain triglycerides (AC-1203) elevates polyunsaturated fatty acids in the parietal cortex of aged dogs: implications for treating age-related cognitive decline. Neurochem Res 2009;34:16191625.

    • Search Google Scholar
    • Export Citation
  • 77. Hall JA, Jewell DE. Feeding healthy Beagles medium-chain triglycerides, fish oil, and carnitine offsets age-related changes in serum fatty acids and carnitine metabolites. PLoS One 2012;7:e49510.

    • Search Google Scholar
    • Export Citation
  • 78. Kashiwaya Y, Takeshima T, Mori N, et al. D-β-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A 2000;97:54405444.

    • Search Google Scholar
    • Export Citation
  • 79. Duthie SJ, Whalley LJ, Collins AR, et al. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002;75:908913.

    • Search Google Scholar
    • Export Citation
  • 80. Bourre JM. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 1: micronutrients. J Nutr Health Aging 2006;10:377385.

    • Search Google Scholar
    • Export Citation
  • 81. Bourre JM. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 2: macronutrients. J Nutr Health Aging 2006;10:386399.

    • Search Google Scholar
    • Export Citation
  • 82. Selhub J, Troen A, Rosenberg IH. B vitamins and the aging brain. Nutr Rev 2010;68:S112S118.

  • 83. de Jager CA, Oulhag A, Jacoby R, et al. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry 2012;27:592600.

    • Search Google Scholar
    • Export Citation
  • 84. Oulhaj A, Jernerén F, Refsum H, et al. Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in mild cognitive impairment. J Alzheimers Dis 2016;50:547557.

    • Search Google Scholar
    • Export Citation
  • 85. Vauzour D, Camprubi-Robles M, Miguel-Kergoat S, et al. Nutrition for the ageing brain: towards evidence for an optimal diet. Ageing Res Rev 2017;35:222240.

    • Search Google Scholar
    • Export Citation
  • 86. Ostrakhovitch EA, Tabidzadeh S. Homocysteine and age-associated disorders. Ageing Res Rev 2019;49:144164.

  • 87. Solfrizzi V, Agosti P, Lozupone M, et al. Nutritional interventions and cognitive-related outcomes in patients with late-life cognitive disorders: a systematic review. Neurosci Biobehav Rev 2018;95:480498.