Neuroketotherapeutics: A modern review of a century-old therapy

Neurochemistry International

Volumn 117, Issue , 2018, Pages 114-125

  Koppel, Scott J ^a   Swerdlow, Russell H ^a,b  

^a UNIVERSITY OF KANSAS MEDICAL CENTER   (United States)

^b UNIVERSITY OF KANSAS SCHOOL OF MEDICINE   (United States)

Author keywords

Alzheimer's disease; Bioenergetics; Ketogenic diet; Ketone bodies; Mitochondria; hydroxybutyrate

Indexed keywords

KETONE; KETONE BODY;

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; BIOCHEMISTRY; CEREBROVASCULAR ACCIDENT; EPILEPSY; EXTRACELLULAR SIGNALING; HISTORY; HUMAN; HUNTINGTON CHOREA; KETOGENESIS; KETOGENIC DIET; KETOLYSIS; LYSIS; MITOCHONDRION; MOLECULAR BIOLOGY; MULTIPLE SCLEROSIS; NEUROKETOTHERAPEUTICS; NEUROLOGIC DISEASE; NEUROPATHOLOGY; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION; THERAPY; TRAUMATIC BRAIN INJURY; ANIMAL; ENERGY METABOLISM; KETOACIDOSIS; METABOLISM; OXIDATIVE STRESS; PHYSIOLOGY; PROCEDURES;

ALZHEIMER DISEASE; ANIMALS; DIET, KETOGENIC; ENERGY METABOLISM; EPILEPSY; HUMANS; KETONE BODIES; KETOSIS; MITOCHONDRIA; OXIDATIVE STRESS;

EID: 85020376066     PISSN: 01970186     EISSN: 18729754     Source Type: Journal    
DOI: 10.1016/j.neuint.2017.05.019     Document Type: Review

References (177)

1. Adam, P.A., Raiha, N., Rahiala, E.L., Kekomaki, M., Oxidation of glucose and D-B-OH-butyrate by the early human fetal brain. Acta Paediatr. Scand. 64 (1975), 17–24.
2. Al-Mudallal, A.S., LaManna, J.C., Lust, W.D., Harik, S.I., Diet-induced ketosis does not cause cerebral acidosis. Epilepsia 37 (1996), 258–261.
3. Apfelbaum, M., Lacatis, D., Reinberg, A., Assan, R., Persisting circadian rhythm in insulin, glucagon, cortisol etc. of healthy young women during caloric restriction (protein diet). Rev. Med. Chir. Soc. Med. Nat. Iasi 76 (1972), 123–130.
4. Baird, G.D., Heitzman, R.J., Hibbitt, K.G., Effects of starvation on intermediary metabolism in the lactating cow. A comparison with metabolic changes occurring during bovine ketosis. Biochem. J. 128 (1972), 1311–1318.
5. Barborka, C.J., Ketogenic diet treatment of epilepsy in adults. J. Am. Med. Assoc. 91 (1928), 73–78.
6. Bartzokis, G., Lu, P.H., Mintz, J., Quantifying age-related myelin breakdown with MRI: novel therapeutic targets for preventing cognitive decline and Alzheimer's disease. J. Alzheimers Dis. 6 (2004), S53–S59.
7. Bartzokis, G., Sultzer, D., Lu, P.H., Nuechterlein, K.H., Mintz, J., Cummings, J.L., Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical “disconnection” in aging and Alzheimer's disease. Neurobiol. Aging 25 (2004), 843–851.
8. Baydyuk, M., Xu, B., BDNF signaling and survival of striatal neurons. Front. Cell. Neurosci., 8, 2014, 254.
9. Bekesi, A., Williamson, D.H., An explanation for ketogenesis by the intestine of the suckling rat: the presence of an active hydroxymethylglutaryl-coenzyme A pathway. Biol. Neonate 58 (1990), 160–165.
10. 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. 283 (2002), E20–E28.
11. 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. 269 (1995), E948–E959.
12. Bough, K.J., Wetherington, J., Hassel, B., Pare, J.F., Gawryluk, J.W., Greene, J.G., Shaw, R., Smith, Y., Geiger, J.D., Dingledine, R.J., Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann. Neurol. 60 (2006), 223–235.
13. Breckenridge, W.C., Kuksis, A., Molecular weight distributions of milk fat triglycerides from seven species. J. Lipid Res. 8 (1967), 473–478.
14. Brinton, R.D., Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease. Adv. Drug Deliv. Rev. 60 (2008), 1504–1511.
15. Bruce, E.D., Konda, S., Dean, D.D., Wang, E.W., Huang, J.H., Little, D.M., Neuroimaging and traumatic brain injury: state of the field and voids in translational knowledge. Mol. Cell Neurosci. 66 (2015), 103–113.
16. Carmichael, O., Schwarz, C., Drucker, D., Fletcher, E., Harvey, D., Beckett, L., Jack, C.R. Jr., Weiner, M., DeCarli, C., Longitudinal changes in white matter disease and cognition in the first year of the Alzheimer disease neuroimaging initiative. Arch. Neurol. 67 (2010), 1370–1378.
17. Castellano, C.A., Nugent, S., Paquet, N., Tremblay, S., Bocti, C., Lacombe, G., Imbeault, H., Turcotte, E., Fulop, T., Cunnane, S.C., Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia. J. Alzheimers Dis. 43 (2015), 1343–1353.
18. Cheng, B., Yang, X., An, L., Gao, B., Liu, X., Liu, S., Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson's disease. Brain Res. 1286 (2009), 25–31.
19. Chong, Z.Z., Kang, J.Q., Maiese, K., Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 106 (2002), 2973–2979.
20. Chong, Z.Z., Kang, J.Q., Maiese, K., Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Br. J. Pharmacol. 138 (2003), 1107–1118.
21. Chong, Z.Z., Li, F., Maiese, K., Activating Akt and the brain's resources to drive cellular survival and prevent inflammatory injury. Histology Histopathol. 20 (2005), 299–315.
22. Chu, A.C., Ho, P.W., Kwok, K.H., Ho, J.W., Chan, K.H., Liu, H.F., Kung, M.H., Ramsden, D.B., Ho, S.L., Mitochondrial UCP4 attenuates MPP+ - and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression. Free Radic. Biol. Med. 46 (2009), 810–820.
23. Cotter, D.G., d'Avignon, D.A., Wentz, A.E., Weber, M.L., Crawford, P.A., Obligate role for ketone body oxidation in neonatal metabolic homeostasis. J. Biol. Chem. 286 (2011), 6902–6910.
24. Cunnane, S.C., Courchesne-Loyer, A., St-Pierre, V., Vandenberghe, C., Pierotti, T., Fortier, M., Croteau, E., Castellano, C.A., 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. 1367 (2016), 12–20.
25. Cunnane, S.C., Crawford, M.A., Survival of the fattest: fat babies were the key to evolution of the large human brain. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 136 (2003), 17–26.
26. de la Monte, S.M., Insulin resistance and Alzheimer's disease. BMB Rep. 42 (2009), 475–481.
27. de Leon, M.J., Convit, A., Wolf, O.T., Tarshish, C.Y., DeSanti, S., Rusinek, H., Tsui, W., Kandil, E., Scherer, A.J., Roche, A., Imossi, A., Thorn, E., Bobinski, M., Caraos, C., Lesbre, P., Schlyer, D., Poirier, J., Reisberg, B., Fowler, J., Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc. Natl. Acad. Sci. U. S. A. 98 (2001), 10966–10971.
28. Deransart, C., Hellwig, B., Heupel-Reuter, M., Leger, J.F., Heck, D., Lucking, C.H., Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy. Epilepsia 44 (2003), 1513–1520.
29. Devi, L., Prabhu, B.M., Galati, D.F., Avadhani, N.G., Anandatheerthavarada, H.K., Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J. Neurosci. 26 (2006), 9057–9068.
30. Dienel, G.A., Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis?. Neurochem. Int. 63 (2013), 244–258.
31. Drysdale, G.R., Lardy, H.A., Fatty acid oxidation by a soluble enzyme system from mitochondria. J. Biol. Chem. 202 (1953), 119–136.
32. Echtay, K.S., Mitochondrial uncoupling proteins–what is their physiological role?. Free Radic. Biol. Med. 43 (2007), 1351–1371.
33. Erecinska, M., Nelson, D., Daikhin, Y., Yudkoff, M., Regulation of GABA level in rat brain synaptosomes: fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J. Neurochem. 67 (1996), 2325–2334.
34. Fernandes, C.G., da Rosa, M.S., Seminotti, B., Pierozan, P., Martell, R.W., Lagranha, V.L., Busanello, E.N., Leipnitz, G., Wajner, M., In vivo experimental evidence that the major metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency induce oxidative stress in striatum of developing rats: a potential pathophysiological mechanism of striatal damage in this disorder. Mol. Genet. Metab. 109 (2013), 144–153.
35. Fernandes, C.G., Pierozan, P., Soares, G.M., Ferreira, F., Zanatta, A., Amaral, A.U., Borges, C.G., Wajner, M., Pessoa-Pureur, R., NMDA receptors and oxidative stress induced by the major metabolites accumulating in HMG lyase deficiency mediate hypophosphorylation of cytoskeletal proteins in brain from adolescent rats: potential mechanisms contributing to the neuropathology of this disease. Neurotox. Res. 28 (2015), 239–252.
36. Freemantle, E., Vandal, M., Tremblay-Mercier, J., Tremblay, S., Blachere, J.C., Begin, M.E., Brenna, J.T., Windust, A., Cunnane, S.C., Omega-3 fatty acids, energy substrates, and brain function during aging. Prostagl. Leukot. Essent. Fat. Acids 75 (2006), 213–220.
37. Fukao, T., Song, X.Q., Mitchell, G.A., Yamaguchi, S., Sukegawa, K., Orii, T., Kondo, N., Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr. Res. 42 (1997), 498–502.
38. Gano, L.B., Patel, M., Rho, J.M., Ketogenic diets, mitochondria, and neurological diseases. J. Lipid Res. 55 (2014), 2211–2228.
39. Garber, A.J., Menzel, P.H., Boden, G., Owen, O.E., Hepatic ketogenesis and gluconeogenesis in humans. J. Clin. Invest. 54 (1974), 981–989.
40. Geyelin, H.R., Fasting as a method for treating epilepsy. Med. Rec. 99 (1921), 1037–1039.
41. Gibbs, M.E., Gibbs, Z., Hertz, L., Rescue of Abeta(1-42)-induced memory impairment in day-old chick by facilitation of astrocytic oxidative metabolism: implications for Alzheimer's disease. J. Neurochem. 109:Suppl. 1 (2009), 230–236.
42. Gibson, C.L., Murphy, A.N., Murphy, S.P., Stroke outcome in the ketogenic state–a systematic review of the animal data. J. Neurochem. 123:Suppl. 2 (2012), 52–57.
43. Gibson, G.E., Xu, H., Chen, H.L., Chen, W., Denton, T.T., Zhang, S., Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines. J. Neurochem. 134 (2015), 86–96.
44. Gu, Z., Jiang, Q., Fu, A.K., Ip, N.Y., Yan, Z., Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex. J. Neurosci. 25 (2005), 4974–4984.
45. Guelpa, G.M.A., La lutte contre l‘e'pilepsie par la de’ sintoxication et par la re'e'ducation alimentaire. Rev. Ther. Medico-Chirurgicale 78 (1911), 8–13.
46. Guzman, M., Blazquez, C., Is there an astrocyte-neuron ketone body shuttle?. Trends Endocrinol. Metab. 12 (2001), 169–173.
47. Hansford, R.G., Hogue, B.A., Mildaziene, V., Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age. J. Bioenerg. Biomembr. 29 (1997), 89–95.
48. Hansson Petersen, C.A., Alikhani, N., Behbahani, H., Wiehager, B., Pavlov, P.F., Alafuzoff, I., Leinonen, V., Ito, A., Winblad, B., Glaser, E., Ankarcrona, M., The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 13145–13150.
49. Hasebe, N., Fujita, Y., Ueno, M., Yoshimura, K., Fujino, Y., Yamashita, T., Soluble beta-amyloid Precursor Protein Alpha binds to p75 neurotrophin receptor to promote neurite outgrowth. PLoS One, 8, 2013, e82321.
50. Hegardt, F.G., Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochem. J. 338:Pt 3 (1999), 569–582.
51. Henderson, S.T., Ketone bodies as a therapeutic for Alzheimer's disease. Neurotherapeutics 5 (2008), 470–480.
52. Henry, M.K., Lynch, J.T., Eapen, A.K., Quelle, F.W., DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway. Blood 98 (2001), 834–841.
53. Hilditch, T.P., The component acids of milk fats of the goat, ewe and mare. Biochem. J. 38 (1944), 443–447.
54. Hirtz, D., Thurman, D.J., Gwinn-Hardy, K., Mohamed, M., Chaudhuri, A.R., Zalutsky, R., How common are the “common” neurologic disorders?. Neurology 68 (2007), 326–337.
55. Ho, J.W., Ho, P.W., Liu, H.F., So, D.H., Chan, K.H., Tse, Z.H., Kung, M.H., Ramsden, D.B., Ho, S.L., UCP4 is a target effector of the NF-kappaB c-Rel prosurvival pathway against oxidative stress. Free Radic. Biol. Med. 53 (2012), 383–394.
56. Ho, P.W., Chu, A.C., Kwok, K.H., Kung, M.H., Ramsden, D.B., Ho, S.L., Knockdown of uncoupling protein-5 in neuronal SH-SY5Y cells: effects on MPP+-induced mitochondrial membrane depolarization, ATP deficiency, and oxidative cytotoxicity. J. Neurosci. Res. 84 (2006), 1358–1366.
57. Ho, P.W., Ho, J.W., Tse, H.M., So, D.H., Yiu, D.C., Liu, H.F., Chan, K.H., Kung, M.H., Ramsden, D.B., Ho, S.L., Uncoupling protein-4 (UCP4) increases ATP supply by interacting with mitochondrial Complex II in neuroblastoma cells. PLoS One, 7, 2012, e32810.
58. Hugo, S.E., Cruz-Garcia, L., Karanth, S., Anderson, R.M., Stainier, D.Y.R., Schlegel, A., A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes & Dev. 26 (2012), 282–293.
59. Insull, W. Jr., Ahrens, E.H. Jr., The fatty acids of human milk from mothers on diets taken ad libitum. Biochem. J. 72 (1959), 27–33.
60. Ishii, K., Sasaki, M., Kitagaki, H., Yamaji, S., Sakamoto, S., Matsuda, K., Mori, E., Reduction of cerebellar glucose metabolism in advanced Alzheimer's disease. J. Nucl. Med. 38 (1997), 925–928.
61. Jang, H.J., Yang, Y.R., Kim, J.K., Choi, J.H., Seo, Y.K., Lee, Y.H., Lee, J.E., Ryu, S.H., Suh, P.G., Phospholipase C-gamma1 involved in brain disorders. Adv. Biol. Regul. 53 (2013), 51–62.
62. Jarrett, S.G., Milder, J.B., Liang, L.P., Patel, M., The ketogenic diet increases mitochondrial glutathione levels. J. Neurochem. 106 (2008), 1044–1051.
63. Ji, A.L., Zhang, X., Chen, W.W., Huang, W.J., Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum. J. Med. Genet., 54, 2017.
64. Juge, N., Gray, J.A., Omote, H., Miyaji, T., Inoue, T., Hara, C., Uneyama, H., Edwards, R.H., Nicoll, R.A., Moriyama, Y., Metabolic control of vesicular glutamate transport and release. Neuron 68 (2010), 99–112.
65. Kalapos, M.P., On the mammalian acetone metabolism: from chemistry to clinical implications. Biochimica Biophysica Acta (BBA) - General Subj. 1621 (2003), 122–139.
66. Kalia, L.V., Lang, A.E., Parkinson's disease. Lancet 386 (2015), 896–912.
67. Kandel, E.R., The molecular biology of memory storage: a dialogue between genes and synapses. Science 294 (2001), 1030–1038.
68. Kang, J.Q., Chong, Z.Z., Maiese, K., Akt1 protects against inflammatory microglial activation through maintenance of membrane asymmetry and modulation of cysteine protease activity. J. Neurosci. Res. 74 (2003), 37–51.
69. Kashiwaya, Y., Pawlosky, R., Markis, W., King, M.T., Bergman, C., Srivastava, S., Murray, A., Clarke, K., Veech, R.L., A ketone ester diet increases brain malonyl-CoA and Uncoupling proteins 4 and 5 while decreasing food intake in the normal Wistar Rat. J. Biol. Chem. 285 (2010), 25950–25956.
70. Keith, H., Experimental convulsions induced by administration of thujone. Arch. Neurol. Psychiatry 34 (1935), 1022–1040.
71. Kim, D.Y., Hao, J., Liu, R., Turner, G., Shi, F.D., Rho, J.M., Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One, 7, 2012, e35476.
72. Kimura, I., Inoue, D., Maeda, T., Hara, T., Ichimura, A., Miyauchi, S., Kobayashi, M., Hirasawa, A., Tsujimoto, G., Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U. S. A. 108 (2011), 8030–8035.
73. Klosinski, L.P., Yao, J., Yin, F., Fonteh, A.N., Harrington, M.G., Christensen, T.A., Trushina, E., Brinton, R.D., White matter lipids as a ketogenic fuel supply in aging female brain: implications for Alzheimer's disease. EBioMedicine 2 (2015), 1888–1904.
74. Kobau, R., Zahran, H., Thurman, D.J., Zack, M.M., Henry, T.R., Schachter, S.C., Price, P.H., Epilepsy surveillance among adults–19 states, behavioral risk factor surveillance system, 2005. MMWR Surveill. Summ. 57 (2008), 1–20.
75. Kogan, J.H., Frankland, P.W., Blendy, J.A., Coblentz, J., Marowitz, Z., Schutz, G., Silva, A.J., Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7 (1997), 1–11.
76. Koppel, I., Timmusk, T., Differential regulation of Bdnf expression in cortical neurons by class-selective histone deacetylase inhibitors. Neuropharmacology 75 (2013), 106–115.
77. Kuczynski, B., Targan, E., Madison, C., Weiner, M., Zhang, Y., Reed, B., Chui, H.C., Jagust, W., White matter integrity and cortical metabolic associations in aging and dementia. Alzheimers Dement. 6 (2010), 54–62.
78. Kwok, K.H., Ho, P.W., Chu, A.C., Ho, J.W., Liu, H.F., Yiu, D.C., Chan, K.H., Kung, M.H., Ramsden, D.B., Ho, S.L., Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity. Free Radic. Biol. Med. 49 (2010), 1023–1035.
79. LaManna, J.C., Salem, N., Puchowicz, M., Erokwu, B., Koppaka, S., Flask, C., Lee, Z., Ketones suppress brain glucose consumption. Adv. Exp. Med. Biol. 645 (2009), 301–306.
80. Lau, D., Bengtson, C.P., Buchthal, B., Bading, H., BDNF reduces toxic extrasynaptic NMDA receptor signaling via synaptic NMDA receptors and nuclear-calcium-induced transcription of inhba/activin a. Cell Rep. 12 (2015), 1353–1366.
81. Le Foll, C., Dunn-Meynell, A.A., Levin, B.E., Role of FAT/CD36 in fatty acid sensing, energy, and glucose homeostasis regulation in DIO and DR rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308 (2015), R188–R198.
82. Le Foll, C., Dunn-Meynell, A.A., Miziorko, H.M., Levin, B.E., Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids. Diabetes 63 (2014), 1259–1269.
83. Le Foll, C., Dunn-Meynell, A.A., Miziorko, H.M., Levin, B.E., Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308 (2015), R872–R878.
84. Le Foll, C., Levin, B.E., Fatty acid-induced astrocyte ketone production and the control of food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310 (2016), R1186–R1192.
85. Lehninger, A.L., Sudduth, H.C., Wise, J.B., D-beta-Hydroxybutyric dehydrogenase of muitochondria. J. Biol. Chem. 235 (1960), 2450–2455.
86. Lim, S., Chesser, A.S., Grima, J.C., Rappold, P.M., Blum, D., Przedborski, S., Tieu, K., D-beta-hydroxybutyrate is protective in mouse models of Huntington's disease. PLoS One, 6, 2011, e24620.
87. Lindblad, B.S., Settergren, G., Feychting, H., Persson, B., Total parenteral nutrition in infants. Blood levels of glucose, lactate, pyruvate, free fatty acids, glycerol, d-beta-hydroxybutyrate, triglycerides, free amino acids and insulin. Acta Paediatr. Scand. 66 (1977), 409–419.
88. Liu, D., Chan, S.L., de Souza-Pinto, N.C., Slevin, J.R., Wersto, R.P., Zhan, M., Mustafa, K., de Cabo, R., Mattson, M.P., Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromolecular Med. 8 (2006), 389–414.
89. Manning, B.D., Cantley, L.C., AKT/PKB signaling: navigating downstream. Cell 129 (2007), 1261–1274.
90. Mantamadiotis, T., Lemberger, T., Bleckmann, S.C., Kern, H., Kretz, O., Martin Villalba, A., Tronche, F., Kellendonk, C., Gau, D., Kapfhammer, J., Otto, C., Schmid, W., Schutz, G., Disruption of CREB function in brain leads to neurodegeneration. Nat. Genet. 31 (2002), 47–54.
91. Marosi, K., Kim, S.W., Moehl, K., Scheibye-Knudsen, M., Cheng, A., Cutler, R., Camandola, S., Mattson, M.P., 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. J. Neurochem. 139 (2016), 769–781.
92. Matsuzaki, H., Tamatani, M., Mitsuda, N., Namikawa, K., Kiyama, H., Miyake, S., Tohyama, M., Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J. Neurochem. 73 (1999), 2037–2046.
93. McNally, M.A., Hartman, A.L., Ketone bodies in epilepsy. J. Neurochem. 121 (2012), 28–35.
94. Melo, T.M., Nehlig, A., Sonnewald, U., Neuronal-glial interactions in rats fed a ketogenic diet. Neurochem. Int. 48 (2006), 498–507.
95. Middleton, B., The existence of ketoacyl-CoA thiolases of differing properties and intracellular localization in ox liver. Biochem. Biophys. Res. Commun. 46 (1972), 508–515.
96. Milder, J.B., Liang, L.P., Patel, M., Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol. Dis. 40 (2010), 238–244.
97. Minichiello, L., Calella, A.M., Medina, D.L., Bonhoeffer, T., Klein, R., Korte, M., Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 36 (2002), 121–137.
98. Minlebaev, M., Khazipov, R., Antiepileptic effects of endogenous beta-hydroxybutyrate in suckling infant rats. Epilepsy Res. 95 (2011), 100–109.
99. Morris, A.A., Cerebral ketone body metabolism. J. Inherit. Metab. Dis. 28 (2005), 109–121.
100. Mosconi, L., de Leon, M., Murray, J.E.L., Lu, J., Javier, E., McHugh, P., Swerdlow, R.H., Reduced mitochondria cytochrome oxidase activity in adult children of mothers with Alzheimer's disease. J. Alzheimers Dis. 27 (2011), 483–490.
101. Mosconi, L., De Santi, S., Brys, M., Tsui, W.H., Pirraglia, E., Glodzik-Sobanska, L., Rich, K.E., Switalski, R., Mehta, P.D., Pratico, D., Zinkowski, R., Blennow, K., de Leon, M.J., Hypometabolism and altered cerebrospinal fluid markers in normal apolipoprotein E E4 carriers with subjective memory complaints. Biol. Psychiatry 63 (2008), 609–618.
102. Mosconi, L., De Santi, S., Li, J., Tsui, W.H., Li, Y., Boppana, M., Laska, E., Rusinek, H., de Leon, M.J., Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol. Aging 29 (2008), 676–692.
103. Mosconi, L., Mistur, R., Switalski, R., Brys, M., Glodzik, L., Rich, K., Pirraglia, E., Tsui, W., De Santi, S., de Leon, M.J., Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease. Neurology 72 (2009), 513–520.
104. Mosconi, L., Tsui, W.H., Herholz, K., Pupi, A., Drzezga, A., Lucignani, G., Reiman, E.M., Holthoff, V., Kalbe, E., Sorbi, S., Diehl-Schmid, J., Perneczky, R., Clerici, F., Caselli, R., Beuthien-Baumann, B., Kurz, A., Minoshima, S., de Leon, M.J., Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J. Nucl. Med. 49 (2008), 390–398.
105. Neal, E.G., Chaffe, H., Schwartz, R.H., Lawson, M.S., Edwards, N., Fitzsimmons, G., Whitney, A., Cross, J.H., The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 7 (2008), 500–506.
106. Nehlig, A., Age-dependent pathways of brain energy metabolism: the suckling rat, a natural model of the ketogenic diet. Epilepsy Res. 37 (1999), 211–221.
107. Nehlig, A., Pereira de Vasconcelos, A., Glucose and ketone body utilization by the brain of neonatal rats. Prog. Neurobiol. 40 (1993), 163–221.
108. Newman, J.C., Verdin, E., Ketone bodies as signaling metabolites. Trends Endocrinol. metabolism TEM 25 (2014), 42–52.
109. Newman, J.C., Verdin, E., β-hydroxybutyrate: much more than a metabolite. Diabetes Res. Clin. Pract. 106 (2014), 173–181.
110. Newport, M.T., VanItallie, T.B., Kashiwaya, Y., King, M.T., Veech, R.L., A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. Alzheimers Dement. 11 (2015), 99–103.
111. Noseworthy, J.H., Lucchinetti, C., Rodriguez, M., Weinshenker, B.G., Multiple sclerosis. N. Engl. J. Med. 343 (2000), 938–952.
112. O'Dwyer, L., Lamberton, F., Bokde, A.L., Ewers, M., Faluyi, Y.O., Tanner, C., Mazoyer, B., O'Neill, D., Bartley, M., Collins, D.R., Coughlan, T., Prvulovic, D., Hampel, H., Multiple indices of diffusion identifies white matter damage in mild cognitive impairment and Alzheimer's disease. PLoS One, 6, 2011, e21745.
113. Offermanns, S., Schwaninger, M., Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation. Trends Mol. Med. 21 (2015), 245–255.
114. Orhan, N., Ugur Yilmaz, C., Ekizoglu, O., Ahishali, B., Kucuk, M., Arican, N., Elmas, I., Gurses, C., Kaya, M., Effects of beta-hydroxybutyrate on brain vascular permeability in rats with traumatic brain injury. Brain Res. 1631 (2016), 113–126.
115. Ovbiagele, B., Nguyen-Huynh, M.N., Stroke epidemiology: advancing our understanding of disease mechanism and therapy. Neurotherapeutics 8 (2011), 319–329.
116. Owada, Y., Utsunomiya, A., Yoshimoto, T., Kondo, H., Expression of mRNA for Akt, serine-threonine protein kinase, in the brain during development and its transient enhancement following axotomy of hypoglossal nerve. J. Mol. Neurosci. 9 (1997), 27–33.
117. Owen, O.E., Kalhan, S.C., Hanson, R.W., The key role of anaplerosis and cataplerosis for citric acid cycle function. J. Biol. Chem. 277 (2002), 30409–30412.
118. Prins, M.L., Fujima, L.S., Hovda, D.A., Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. J. Neurosci. Res. 82 (2005), 413–420.
119. Prins, M.L., Lee, S.M., Fujima, L.S., Hovda, D.A., Increased cerebral uptake and oxidation of exogenous betaHB improves ATP following traumatic brain injury in adult rats. J. Neurochem. 90 (2004), 666–672.
120. Prins, M.L., Matsumoto, J.H., The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J. Lipid Res. 55 (2014), 2450–2457.
121. Puchowicz, M.A., Zechel, J., Valerio, J., Emancipator, D., Xu, K., Pundik, S., LaManna, J.C., Lust, W.D., Neuroprotection in diet induced ketotic rat brain following focal ischemia. J. Cereb. blood flow metabolism official J. Int. Soc. Cereb. Blood Flow Metabolism 28 (2008), 1907–1916.
122. Puisac, B., Ramos, M., Arnedo, M., Menao, S., Gil-Rodriguez, M.C., Teresa-Rodrigo, M.E., Pie, A., de Karam, J.C., Wesselink, J.J., Gimenez, I., Ramos, F.J., Casals, N., Gomez-Puertas, P., Hegardt, F.G., Pie, J., Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway. Mol. Biol. Rep. 39 (2012), 4777–4785.
123. Rahman, M., Muhammad, S., Khan, M.A., Chen, H., Ridder, D.A., Muller-Fielitz, H., Pokorna, B., Vollbrandt, T., Stolting, I., Nadrowitz, R., Okun, J.G., Offermanns, S., Schwaninger, M., The beta-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages. Nat. Commun., 5, 2014, 3944.
124. Ramagopalan, S.V., Sadovnick, A.D., Epidemiology of multiple sclerosis. Neurol. Clin. 29 (2011), 207–217.
125. Ramsden, D.B., Ho, P.W., Ho, J.W., Liu, H.F., So, D.H., Tse, H.M., Chan, K.H., Ho, S.L., Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction. Brain Behav. 2 (2012), 468–478.
126. Randle, P.J., Garland, P.B., Hales, C.N., Newsholme, E.A., The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1 (1963), 785–789.
127. Rardin, M.J., Newman, J.C., Held, J.M., Cusack, M.P., Sorensen, D.J., Li, B., Schilling, B., Mooney, S.D., Kahn, C.R., Verdin, E., Gibson, B.W., Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc. Natl. Acad. Sci. U. S. A. 110 (2013), 6601–6606.
128. 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 25 (2004), 311–314.
129. 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. 101 (2004), 284–289.
130. Rodriguez-Perdigon, M., Solas, M., Moreno-Aliaga, M.J., Ramirez, M.J., Lipoic acid improves neuronal insulin signalling and rescues cognitive function regulating VGlut1 expression in high-fat-fed rats: implications for Alzheimer's disease. Biochim. Biophys. Acta 1862 (2016), 511–517.
131. Rosenbloom, M.H., Alkalay, A., Agarwal, N., Baker, S.L., O'Neil, J.P., Janabi, M., Yen, I.V., Growdon, M., Jang, J., Madison, C., Mormino, E.C., Rosen, H.J., Gorno-Tempini, M.L., Weiner, M.W., Miller, B.L., Jagust, W.J., Rabinovici, G.D., Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution. Neurology 76 (2011), 1789–1796.
132. Ross, C.A., Tabrizi, S.J., Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 10 (2011), 83–98.
133. Rui, L., Energy metabolism in the liver. Compr. Physiol. 4 (2014), 177–197.
134. Samala, R., Klein, J., Borges, K., The ketogenic diet changes metabolite levels in hippocampal extracellular fluid. Neurochem. Int. 58 (2011), 5–8.
135. Selfridge, J.E., Wilkins, H.M., E, L., Carl, S.M., Koppel, S., Funk, E., Fields, T., Lu, J., Tang, E.P., Slawson, C., Wang, W., Zhu, H., Swerdlow, R.H., Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure. J. Bioenerg. Biomembr. 47 (2015), 1–11.
136. Shimazu, T., Hirschey, M.D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C.A., Lim, H., Saunders, L.R., Stevens, R.D., Newgard, C.B., Farese, R.V. Jr., de Cabo, R., Ulrich, S., Akassoglou, K., Verdin, E., Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339 (2013), 211–214.
137. Silva, A.J., Kogan, J.H., Frankland, P.W., Kida, S., CREB and memory. Annu. Rev. Neurosci. 21 (1998), 127–148.
138. Simeone, T.A., Matthews, S.A., Samson, K.K., Simeone, K.A., Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. Exp. Neurol. 287 (2017), 54–64.
139. Sleiman, S.F., Henry, J., Al-Haddad, R., El Hayek, L., Abou Haidar, E., Stringer, T., Ulja, D., Karuppagounder, S.S., Holson, E.B., Ratan, R.R., Ninan, I., Chao, M.V., Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body beta-hydroxybutyrate. Elife, 5, 2016.
140. Spulber, G., Niskanen, E., MacDonald, S., Smilovici, O., Chen, K., Reiman, E.M., Jauhiainen, A.M., Hallikainen, M., Tervo, S., Wahlund, L.O., Vanninen, R., Kivipelto, M., Soininen, H., Whole brain atrophy rate predicts progression from MCI to Alzheimer's disease. Neurobiol. Aging 31 (2010), 1601–1605.
141. Srivastava, S., Kashiwaya, Y., King, M.T., Baxa, U., Tam, J., Niu, G., Chen, X., Clarke, K., Veech, R.L., Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. Faseb J. 26 (2012), 2351–2362.
142. Stilling, R.M., van de Wouw, M., Clarke, G., Stanton, C., Dinan, T.G., Cryan, J.F., The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis?. Neurochem. Int. 99 (2016), 110–132.
143. Suh, P.G., Park, J.I., Manzoli, L., Cocco, L., Peak, J.C., Katan, M., Fukami, K., Kataoka, T., Yun, S., Ryu, S.H., Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep. 41 (2008), 415–434.
144. Sullivan, P.G., Rippy, N.A., Dorenbos, K., Concepcion, R.C., Agarwal, A.K., Rho, J.M., The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann. Neurol. 55 (2004), 576–580.
145. Suzuki, M., Suzuki, M., Kitamura, Y., Mori, S., Sato, K., Dohi, S., Sato, T., Matsuura, A., Hiraide, A., Beta-hydroxybutyrate, a cerebral function improving agent, protects rat brain against ischemic damage caused by permanent and transient focal cerebral ischemia. Jpn. J. Pharmacol. 89 (2002), 36–43.
146. Suzuki, M., Suzuki, M., Sato, K., Dohi, S., Sato, T., Matsuura, A., Hiraide, A., Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn. J. Pharmacol. 87 (2001), 143–150.
147. Swerdlow, R.H., Brain aging, Alzheimer's disease, and mitochondria. Biochim. Biophys. Acta 1812 (2011), 1630–1639.
148. Swerdlow, R.H., Alzheimer's disease pathologic cascades: who comes first, what drives what. Neurotox. Res. 22 (2012), 182–194.
149. Swerdlow, R.H., beta-Apptists and Tauists, it is time for a sermon from the book of biogenesis. J. Neurochem. 120 (2012), 347–349.
150. Swerdlow, R.H., Mitochondria and cell bioenergetics: increasingly recognized components and a possible etiologic cause of Alzheimer's disease. Antioxid. Redox Signal 16 (2012), 1434–1455.
151. Swerdlow, R.H., Comment: BDNF, fitness, and the brain. Neurology, 83, 2014, 1351.
152. Tanner, G.R., Lutas, A., Martinez-Francois, J.R., Yellen, G., Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons. J. Neurosci. 31 (2011), 8689–8696.
153. Temkin, O., The Falling Sickness: a History of Epilepsy from the Greeks to the Beginnings of Modern Neurology. 1994, Johns Hopkins University Press.
154. Tieu, K., Perier, C., Caspersen, C., Teismann, P., Wu, D.C., Yan, S.D., Naini, A., Vila, M., Jackson-Lewis, V., Ramasamy, R., Przedborski, S., D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J. Clin. Invest. 112 (2003), 892–901.
155. Vanitallie, T.B., Nonas, C., Di Rocco, A., Boyar, K., Hyams, K., Heymsfield, S.B., Treatment of Parkinson disease with diet-induced hyperketonemia: a feasibility study. Neurology 64 (2005), 728–730.
156. Vazquez-Vela, M.E., Torres, N., Tovar, A.R., White adipose tissue as endocrine organ and its role in obesity. Arch. Med. Res. 39 (2008), 715–728.
157. Vijay, N., Morris, M.E., Role of monocarboxylate transporters in drug delivery to the brain. Curr. Pharm. Des. 20 (2014), 1487–1498.
158. Villain, N., Fouquet, M., Baron, J.C., Mezenge, F., Landeau, B., de La Sayette, V., Viader, F., Eustache, F., Desgranges, B., Chetelat, G., Sequential relationships between grey matter and white matter atrophy and brain metabolic abnormalities in early Alzheimer's disease. Brain 133 (2010), 3301–3314.
159. 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-beta (Abeta) deposition. Proc. Natl. Acad. Sci. U. S. A. 107 (2010), 17763–17767.
160. Votyakova, T.V., Reynolds, I.J., DeltaPsi(m)-Dependent and -independent production of reactive oxygen species by rat brain mitochondria. J. Neurochem. 79 (2001), 266–277.
161. Wang, W., Wang, L., Lu, J., Siedlak, S.L., Fujioka, H., Liang, J., Jiang, S., Ma, X., Jiang, Z., da Rocha, E.L., Sheng, M., Choi, H., Lerou, P.H., Li, H., Wang, X., The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat. Med. 22 (2016), 869–878.
162. Wang, Z.J., Bergqvist, C., Hunter, J.V., Jin, D., Wang, D.J., Wehrli, S., Zimmerman, R.A., In vivo measurement of brain metabolites using two-dimensional double-quantum MR spectroscopy–exploration of GABA levels in a ketogenic diet. Magn. Reson Med. 49 (2003), 615–619.
163. Wei, Z., Chigurupati, S., Bagsiyao, P., Henriquez, A., Chan, S.L., The brain uncoupling protein UCP4 attenuates mitochondrial toxin-induced cell death: role of extracellular signal-regulated kinases in bioenergetics adaptation and cell survival. Neurotox. Res. 16 (2009), 14–29.
164. Wheless, J.W., History of the ketogenic diet. Epilepsia 49:Suppl. 8 (2008), 3–5.
165. Wilder, R.M., The effect of ketonemia on the course of epilepsy. Mayo Clin. Bull., 2, 1921, 307.
166. Wilkins, H.M., Swerdlow, R.H., Amyloid precursor protein processing and bioenergetics. Brain Res. Bull., 2016 (in press).
167. Winkler, E.A., Nishida, Y., Sagare, A.P., Rege, S.V., Bell, R.D., Perlmutter, D., Sengillo, J.D., Hillman, S., Kong, P., Nelson, A.R., Sullivan, J.S., Zhao, Z., Meiselman, H.J., Wenby, R.B., Soto, J., Abel, E.D., Makshanoff, J., Zuniga, E., De Vivo, D.C., Zlokovic, B.V., GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci. 18 (2015), 521–530.
168. Won, Y.J., Lu, V.B., Puhl, H.L. 3rd, Ikeda, S.R., beta-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J. Neurosci. 33 (2013), 19314–19325.
169. Woodyatt, R.T., Objects and method of diet adjustment in diabetes. Archives Intern. Med. 28 (1921), 125–141.
170. Xie, Z., Zhang, D., Chung, D., Tang, Z., Huang, H., Dai, L., Qi, S., Li, J., Colak, G., Chen, Y., Xia, C., Peng, C., Ruan, H., Kirkey, M., Wang, D., Jensen, L.M., Kwon, O.K., Lee, S., Pletcher, S.D., Tan, M., Lombard, D.B., White, K.P., Zhao, H., Li, J., Roeder, R.G., Yang, X., Zhao, Y., Metabolic regulation of gene expression by histone lysine beta-hydroxybutyrylation. Mol. Cell 62 (2016), 194–206.
171. Yang, X., Cheng, B., Neuroprotective and anti-inflammatory activities of ketogenic diet on MPTP-induced neurotoxicity. J. Mol. Neurosci. 42 (2010), 145–153.
172. Yao, J., Chen, S., Mao, Z., Cadenas, E., Brinton, R.D., 2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease. PLoS One, 6, 2011, e21788.
173. Yao, J., Rettberg, J.R., Klosinski, L.P., Cadenas, E., Brinton, R.D., Shift in brain metabolism in late onset Alzheimer's disease: implications for biomarkers and therapeutic interventions. Mol. Asp. Med. 32 (2011), 247–257.
174. Yin, J.X., Maalouf, M., Han, P., Zhao, M., Gao, M., Dharshaun, T., Ryan, C., Whitelegge, J., Wu, J., Eisenberg, D., Reiman, E.M., Schweizer, F.E., Shi, J., Ketones block amyloid entry and improve cognition in an Alzheimer's model. Neurobiol. Aging 39 (2016), 25–37.
175. Zhao, S., Fu, J., Liu, X., Wang, T., Zhang, J., Zhao, Y., Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats. Neurol. Res. 34 (2012), 400–407.
176. Zhao, W., Varghese, M., Vempati, P., Dzhun, A., Cheng, A., Wang, J., Lange, D., Bilski, A., Faravelli, I., Pasinetti, G.M., Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease. PLoS One, 7, 2012, e49191.
177. Zhao, Z., Lange, D.J., Voustianiouk, A., MacGrogan, D., Ho, L., Suh, J., Humala, N., Thiyagarajan, M., Wang, J., Pasinetti, G.M., A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci., 7, 2006, 29.