Brain glucose and acetoacetate metabolism: A comparison of young and older adults

Neurobiology of Aging

Volumn 35, Issue 6, 2014, Pages 1386-1395

  Nugent, Scott ^a   Tremblay, Sebastien ^a,b   Chen, Kewei W ^c   Ayutyanont, Napatkamon ^c   Roontiva, Auttawut ^c   Castellano, Christian Alexandre ^a   Fortier, Melanie ^a   Roy, Maggie ^a   Courchesne Loyer, Alexandre ^a   Bocti, Christian ^a   Lepage, Martin ^a,b   Turcotte, Eric ^a,b   Fulop, Tamas ^a   Reiman, Eric M ^c   Cunnane, Stephen C ^a  

^a UNIVERSITÉ DE SHERBROOKE   (Canada)

^b UNIVERSITY OF SHERBROOKE   (Canada)

^c BANNER ALZHEIMER S INSTITUTE   (United States)

Author keywords

Acetoacetate; Aging; Brain; FDG; Ketones; Magnetic resonance imaging; Positron emission tomography

Indexed keywords

ACETOACETIC ACID; FLUORODEOXYGLUCOSE F 18; GLUCOSE; HEMOGLOBIN A1C; IRBESARTAN; PANTOPRAZOLE; RAMIPRIL; RISEDRONIC ACID; TELMISARTAN; ACETOACETIC ACID DERIVATIVE; KETONE;

ADULT; AGED; AGING; ARTICLE; BODY MASS; BRAIN MAPPING; BRAIN METABOLISM; CATABOLISM; CAUDATE NUCLEUS; CONTROLLED STUDY; ENERGY METABOLISM; FEMALE; GENETIC PREDISPOSITION; GLUCOSE METABOLISM; GLUCOSE TRANSPORT; HEMOGLOBIN BLOOD LEVEL; HUMAN; HYPERTENSION; IMAGE ANALYSIS; IMAGE PROCESSING; MAJOR CLINICAL STUDY; MALE; MINI MENTAL STATE EXAMINATION; NEUROIMAGING; OSTEOPOROSIS; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; SYSTOLIC BLOOD PRESSURE; VERY ELDERLY; YOUNG ADULT; ADOLESCENT; BRAIN; COMPARATIVE STUDY; METABOLISM; NUCLEAR MAGNETIC RESONANCE IMAGING;

ACETOACETATES; ADOLESCENT; ADULT; AGED; AGED, 80 AND OVER; AGING; BRAIN; FEMALE; GLUCOSE; HUMANS; KETONES; MAGNETIC RESONANCE IMAGING; MALE; POSITRON-EMISSION TOMOGRAPHY; YOUNG ADULT;

EID: 84903362456     PISSN: 01974580     EISSN: 15581497     Source Type: Journal    
DOI: 10.1016/j.neurobiolaging.2013.11.027     Document Type: Article

References (62)

1. Amiel S.A., Archibald H.R., Chusney G., Williams A.J., Gale E.A. Ketone infusion lowers hormonal responses to hypoglycaemia: evidence for acute cerebral utilization of a non-glucose fuel. Clin. Sci. (Lond) 1991, 81:189-194.
2. Andreason P.J., Zametkin A.J., Guo A.C., Baldwin P., Cohen R.M. Gender-related differences in regional cerebral glucose metabolism in normal volunteers. Psychiatry Res. 1994, 51:175-183.
3. Auestad N., Korsak R.A., Morrow J.W., Edmond J. Fatty acid oxidation and ketogenesis by astrocytes in primary culture. J.Neurochem. 1991, 56:1376-1386.
4. Balasse E.O., Fery F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab. Rev. 1989, 5:247-270.
5. Benjamini Y., Drai D., Elmer G., Kafkafi N., Golani I. Controlling the false discovery rate in behavior genetics research. Behav. Brain Res. 2001, 125:279-284.
6. Bentourkia M., Tremblay S., Pifferi F., Rousseau J., Lecomte R., Cunnane S. PET study of 11C-acetoacetate kinetics in rat brain during dietary treatments affecting ketosis. Am. J. Physiol. Endocrinol. Metab. 2009, 296:E796-E801. 10.1152/ajpendo.90644.2008.
7. Blomqvist G., Alvarsson M., Grill V., Von Heijne G., Ingvar M., Thorell J.O., Stone-Elander S., Widen L., Ekberg K. Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients. Am. J. Physiol. Endocrinol. Metab. 2002, 283:E20-E28. 10.1152/ajpendo.00294.2001.
8. Blomqvist G., Thorell J.O., Ingvar M., Grill V., Widen L., Stone-Elander S. Use of R-beta-[1-11C]hydroxybutyrate in PET studies of regional cerebral uptake of ketone bodies in humans. Am. J. Physiol. 1995, 269(5 Pt 1):E948-E959.
9. Cahill G.F. Fuel metabolism in starvation. Annu. Rev. Nutr. 2006, 26:1-22. 10.1146/annurev.nutr.26.061505.111258.
10. Chetelat G., Landeau B., Salmon E., Yakushev I., Bahri M.A., Mezenge F., Perrotin A., Bastin C., Manrique A., Scheurich A., Scheckenberger M., Desgranges B., Eustache F., Fellgiebel A. Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity. Neuroimage 2013, 76:167-177. 10.1016/j.neuroimage.2013.03.009.
11. Courchesne-Loyer A., Fortier M., Tremblay-Mercier J., Chouinard-Watkins R., Roy M., Nugent S., Castellano C.A., Cunnane S.C. Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: estimated potential contribution to brain energy metabolism. Nutrition 2013, 29:635-640. 10.1016/j.nut.2012.09.009.
12. Cremer J.E. Substrate utilization and brain development. J.Cereb. Blood Flow Metab. 1982, 2:394-407. 10.1038/jcbfm.1982.43.
13. Cunnane S., Nugent S., Roy M., Courchesne-Loyer A., Croteau E., Tremblay S., Castellano A., Pifferi F., Bocti C., Paquet N., Begdouri H., Bentourkia M., Turcotte E., Allard M., Barberger-Gateau P., Fulop T., Rapoport S.I. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition 2011, 27:3-20. doi:S0899-9007(10)00280-7 [pii]. doi:10.1016/j.nut.2010.07.021.
14. Curiati P.K., Tamashiro-Duran J.H., Duran F.L., Buchpiguel C.A., Squarzoni P., Romano D.C., Vallada H., Menezes P.R., Scazufca M., Busatto G.F., Alves T.C. Age-related metabolic profiles in cognitively healthy elders: results from a voxel-based [18F]fluorodeoxyglucose-positron-emission tomography study with partial volume effects correction. AJNR Am. J. Neuroradiol. 2011, 32:560-565. 10.3174/ajnr.A2321.
15. De Santi S., de Leon M.J., Convit A., Tarshish C., Rusinek H., Tsui W.H., Sinaiko E., Wang G.J., Bartlet E., Volkow N. Age-related changes in brain: II. Positron emission tomography of frontal and temporal lobe glucose metabolism in normal subjects. Psychiatr. Q. 1995, 66:357-370.
16. Esposito G., Giovacchini G., Liow J.S., Bhattacharjee A.K., Greenstein D., Schapiro M., Hallett M., Herscovitch P., Eckelman W.C., Carson R.E., Rapoport S.I. Imaging neuroinflammation in Alzheimer's disease with radiolabeled arachidonic acid and PET. J.Nucl. Med. 2008, 49:1414-1421. 10.2967/jnumed.107.049619.
17. Folstein M.F., Folstein S.E., McHugh P.R. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J.Psychiatr. Res. 1975, 12:189-198.
18. Gottstein U., Muller W., Berghoff W., Gartner H., Held K. [Utilization of non-esterified fatty acids and ketone bodies in human brain]. Klin. Wochenschr. 1971, 49:406-411.
19. Graham M.M., Muzi M., Spence A.M., O'Sullivan F., Lewellen T.K., Link J.M., Krohn K.A. The FDG lumped constant in normal human brain. J.Nucl. Med. 2002, 43:1157-1166.
20. Hasselbalch S.G., Knudsen G.M., Jakobsen J., Hageman L.P., Holm S., Paulson O.B. Blood-brain barrier permeability of glucose and ketone bodies during short-term starvation in humans. Am. J. Physiol. 1995, 268(6 Pt 1):E1161-E1166.
21. Hasselbalch S.G., Madsen P.L., Hageman L.P., Olsen K.S., Justesen N., Holm S., Paulson O.B. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am. J. Physiol. 1996, 270(5 Pt 1):E746-E751.
22. Henderson S.T. Ketone bodies as a therapeutic for Alzheimer's disease. Neurotherapeutics 2008, 5:470-480. 10.1016/j.nurt.2008.05.004.
23. Ibanez V., Pietrini P., Alexander G.E., Furey M.L., Teichberg D., Rajapakse J.C., Rapoport S.I., Schapiro M.B., Horwitz B. Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease. Neurology 1998, 50:1585-1593.
24. Ibanez V., Pietrini P., Furey M.L., Alexander G.E., Millet P., Bokde A.L., Teichberg D., Schapiro M.B., Horwitz B., Rapoport S.I. Resting state brain glucose metabolism is not reduced in normotensive healthy men during aging, after correction for brain atrophy. Brain Res. Bull 2004, 63:147-154. 10.1016/j.brainresbull.2004.02.003.
25. Kalpouzos G., Chetelat G., Baron J.C., Landeau B., Mevel K., Godeau C., Barre L., Constans J.M., Viader F., Eustache F., Desgranges B. Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging. Neurobiol. Aging 2009, 30:112-124. 10.1016/j.neurobiolaging.2007.05.019.
26. Kantarci K., Senjem M.L., Lowe V.J., Wiste H.J., Weigand S.D., Kemp B.J., Frank A.R., Shiung M.M., Boeve B.F., Knopman D.S., Petersen R.C., Jack C.R. Effects of age on the glucose metabolic changes in mild cognitive impairment. AJNR Am. J. Neuroradiol. 2010, 31:1247-1253. 10.3174/ajnr.A2070.
27. Krikorian R., Shidler M.D., Dangelo K., Couch S.C., Benoit S.C., Clegg D.J. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol. Aging 2012, 33:425.e19-425.e27. 10.1016/j.neurobiolaging.2010.10.006.
28. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab. Res. Rev. 1999, 15:412-426.
29. Langbaum J.B., Chen K., Lee W., Reschke C., Bandy D., Fleisher A.S., Alexander G.E., Foster N.L., Weiner M.W., Koeppe R.A., Jagust W.J., Reiman E.M. Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neuroimage 2009, 45:1107-1116. 10.1016/j.neuroimage.2008.12.072.
30. Li Y., Rinne J.O., Mosconi L., Pirraglia E., Rusinek H., DeSanti S., Kemppainen N., Nagren K., Kim B.C., Tsui W., de Leon M.J. Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging 2008, 35:2169-2181. 10.1007/s00259-008-0833-y.
31. Lying-Tunell U., Lindblad B.S., Malmlund H.O., Persson B. Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids. Acta Neurol. Scand. 1981, 63:337-350.
32. Maalouf M., Rho J.M., Mattson M.P. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res. Rev. 2009, 59:293-315. 10.1016/j.brainresrev.2008.09.002.
33. Mamelak M. Sporadic Alzheimer's disease: the starving brain. J.Alzheimers Dis. 2012, 31:459-474. 10.3233/JAD-2012-120370.
34. Marano C.M., Workman C.I., Kramer E., Hermann C.R., Ma Y., Dhawan V., Chaly T., Eidelberg D., Smith G.S. Longitudinal studies of cerebral glucose metabolism in late-life depression and normal aging. Int. J. Geriatr. Psychiatry 2012, 10.1002/gps.3840.
35. Mitchell G.A., Kassovska-Bratinova S., Boukaftane Y., Robert M.F., Wang S.P., Ashmarina L., Lambert M., Lapierre P., Potier E. Medical aspects of ketone body metabolism. Clin. Invest. Med. 1995, 18:193-216.
36. Morris A.A. Cerebral ketone body metabolism. J.Inherit. Metab. Dis. 2005, 28:109-121. 10.1007/s10545-005-5518-0.
37. Mosconi L., Brys M., Switalski R., Mistur R., Glodzik L., Pirraglia E., Tsui W., De Santi S., de Leon M.J. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proc. Natl. Acad. Sci. U.S.A 2007, 104:19067-19072. 10.1073/pnas.0705036104.
38. Mosconi L., Mistur R., Switalski R., Tsui W.H., Glodzik L., Li Y., Pirraglia E., De Santi S., Reisberg B., Wisniewski T., de Leon M.J. FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer's disease. Eur. J. Nucl. Med. Mol. Imaging 2009, 36:811-822. 10.1007/s00259-008-1039-z.
39. Nehlig A. Brain uptake and metabolism of ketone bodies in animal models. Prostaglandins Leukot. Essent. Fatty Acids 2004, 70:265-275. 10.1016/j.plefa.2003.07.006.
40. Owen O.E., Morgan A.P., Kemp H.G., Sullivan J.M., Herrera M.G., Cahill G.F. Brain metabolism during fasting. J.Clin. Invest. 1967, 46:1589-1595. 10.1172/JCI105650.
41. Page M.A., Williamson D.H. Enzymes of ketone-body utilisation in human brain. Lancet 1971, 2:66-68.
42. Patlak C.S., Blasberg R.G., Fenstermacher J.D. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J.Cereb. Blood Flow Metab. 1983, 3:1-7. 10.1038/jcbfm.1983.1.
43. Phelps M.E., Huang S.C., Hoffman E.J., Selin C., Sokoloff L., Kuhl D.E. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann. Neurol. 1979, 6:371-388. 10.1002/ana.410060502.
44. Pierre K., Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J.Neurochem. 2005, 94:1-14. 10.1111/j.1471-4159.2005.03168.x.
45. Pifferi F., Tremblay S., Croteau E., Fortier M., Tremblay-Mercier J., Lecomte R., Cunnane S.C. Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats. Nutr. Neurosci. 2011, 14:51-58. 10.1179/1476830510Y.0000000001.
46. Quarantelli M., Berkouk K., Prinster A., Landeau B., Svarer C., Balkay L., Alfano B., Brunetti A., Baron J.C., Salvatore M. Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction. J.Nucl. Med. 2004, 45:192-201.
47. Reger M.A., Henderson S.T., Hale C., Cholerton B., Baker L.D., Watson G.S., Hyde K., Chapman D., Craft S. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol. Aging 2004, 25:311-314. 10.1016/S0197-4580(03)00087-3.
48. Reiman E.M., Chen K., Alexander G.E., Caselli R.J., Bandy D., Osborne D., Saunders A.M., Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc. Natl. Acad. Sci. U.S.A 2004, 101:284-289. 10.1073/pnas.2635903100.
49. Reiman E.M., Chen K., Alexander G.E., Caselli R.J., Bandy D., Osborne D., Saunders A.M., Hardy J. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc. Natl. Acad. Sci. U.S.A 2005, 102:8299-8302. 10.1073/pnas.0500579102.
50. Robinson A.M., Williamson D.H. Physiological roles of ketone bodiesas substrates and signals in mammalian tissues. Physiol. Rev. 1980, 60:143-187.
51. Roy M., Nugent S., Tremblay-Mercier J., Tremblay S., Courchesne-Loyer A., Beaudoin J.F., Tremblay L., Descoteaux M., Lecomte R., Cunnane S.C. The ketogenic diet increases brain glucose and ketone uptake in aged rats: a dual tracer PET and volumetric MRI study. Brain Res. 2012, 1488:14-23. 10.1016/j.brainres.2012.10.008.
52. Scheef L., Spottke A., Daerr M., Joe A., Striepens N., Kolsch H., Popp J., Daamen M., Gorris D., Heneka M.T., Boecker H., Biersack H.J., Maier W., Schild H.H., Wagner M., Jessen F. Glucose metabolism, gray matterstructure, and memory decline in subjective memory impairment. Neurology 2012, 79:1332-1339. 10.1212/WNL.0b013e31826c1a8d.
53. Swerdlow R.H. Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies. Pharmaceuticals (Basel) 2009, 2:150-167. 10.3390/ph2030150.
54. Tremblay S., Ouellet R., Rodrigue S., Langlois R., Benard F., Cunnane S.C. Automated synthesis of 11C-acetoacetic acid, a key alternate brain fuel to glucose. Appl. Radiat. Isot. 2007, 65:934-940. 10.1016/j.apradiso.2007.03.015.
55. Vaishnavi S.N., Vlassenko A.G., Rundle M.M., Snyder A.Z., Mintun M.A., Raichle M.E. Regional aerobic glycolysis in the human brain. Proc.Natl. Acad. Sci. U.S.A 2010, 107:17757-17762. 10.1073/pnas.1010459107.
56. Veech R.L., Chance B., Kashiwaya Y., Lardy H.A., Cahill G.F. Ketone bodies, potential therapeutic uses. IUBMB Life 2001, 51:241-247. 10.1080/152165401753311780.
57. Veneman T., Mitrakou A., Mokan M., Cryer P., Gerich J. Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes 1994, 43:1311-1317.
58. Vlassenko A.G., Vaishnavi S.N., Couture L., Sacco D., Shannon B.J., Mach R.H., Morris J.C., Raichle M.E., Mintun M.A. Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition. Proc. Natl. Acad. Sci. U.S.A 2010, 107:17763-17767. 10.1073/pnas.1010461107.
59. Willis M.W., Ketter T.A., Kimbrell T.A., George M.S., Herscovitch P., Danielson A.L., Benson B.E., Post R.M. Age, sex and laterality effects on cerebral glucose metabolism in healthy adults. Psychiatry Res. 2002, 114:23-37.
60. Yanase D., Matsunari I., Yajima K., Chen W., Fujikawa A., Nishimura S., Matsuda H., Yamada M. Brain FDG PET study of normal aging in Japanese: effect of atrophy correction. Eur. J. Nucl. Med. Mol. Imaging 2005, 32:794-805. 10.1007/s00259-005-1767-2.
61. Yuan X., Shan B., Ma Y., Tian J., Jiang K., Cao Q., Wang R. Multi-center study on Alzheimer's disease using FDG PET: group and individual analyses. J.Alzheimers Dis. 2010, 19:927-935. 10.3233/JAD-2010-1287.
62. Zhou S., Chen K., Reiman E.M., Li D.M., Shan B. Amethod of generating image-derived input function in a quantitative (1)(8)F-FDGPET study based on the shape of the input function curve. Nucl.Med. Commun. 2011, 32:1121-1127. 10.1097/MNM.0b013e32834abd1b.