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Changes in cerebral metabolism during ketogenic diet in patients with primary brain tumors: 1H-MRS study

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Abstract

Normal brain cells depend on glucose metabolism, yet they have the flexibility to switch to the usage of ketone bodies during caloric restriction. In contrast, tumor cells lack genomic and metabolic flexibility and are largely dependent on glucose. Ketogenic-diet (KD) was suggested as a therapeutic option for malignant brain cancer. This study aimed to detect metabolic brain changes in patients with malignant brain gliomas on KD using proton magnetic-resonance-spectroscopy (1H-MRS). Fifty MR scans were performed longitudinally in nine patients: four patients with recurrent glioblastoma (GB) treated with KD in addition to bevacizumab; one patient with gliomatosis-cerebri treated with KD only; and four patients with recurrent GB who did not receive KD. MR scans included conventional imaging and 1H-MRS acquired from normal appearing-white-matter (NAWM) and lesion. High adherence to KD was obtained only in two patients, based on high urine ketones; in these two patients ketone bodies, Acetone and Acetoacetate were detected in four MR spectra—three within the NAWM and one in the lesion area −4 and 25 months following initiation of the diet. No ketone-bodies were detected in the control group. In one patient with gliomatosis-cerebri, who adhered to the diet for 3 years and showed stable disease, an increase in glutamin + glutamate and reduction in N-Acetyl-Aspartate and myo-inositol were detected during KD. 1H-MRS was able to detect ketone-bodies in patients with brain tumors who adhered to KD. Yet it remains unclear whether accumulation of ketone bodies is due to increased brain uptake or decreased utilization of ketone bodies within the brain.

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References

  1. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    Article  CAS  Google Scholar 

  2. Tanaka S, Louis DN, Curry WT, Batchelor TT, Dietrich J (2013) Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end?. Nat Rev Clin Oncol 10: 14–26 doi:10.1038/nrclinonc.2012.204

    Article  CAS  PubMed  Google Scholar 

  3. Wilder R (1921) The effects of ketonemia on the course of epilepsy. Mayo Clin Proc 2:307–308

    Google Scholar 

  4. Kinsman SL, Vining EP, Quaskey SA, Mellits D, Freeman JM (1992) Efficacy of the ketogenic diet for intractable seizure disorders: review of 58 cases. Epilepsia 33:1132–1136

    Article  CAS  Google Scholar 

  5. Evangeliou A, Vlachonikolis I, Mihailidou H, Spilioti M, Skarpalezou A, Makaronas N, Prokopiou A, Christodoulou P, Liapi-Adamidou G, Helidonis E, Sbyrakis S, Smeitink J (2003) Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol 18:113–118

    Article  Google Scholar 

  6. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC (2009) Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) 6:31

    Article  Google Scholar 

  7. Schmidt M, Pfetzer N, Schwab M, Strauss I, Kammerer U (2011) Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. Nutr Metab (Lond) 8:54

    Article  CAS  Google Scholar 

  8. Zuccoli G, Marcello N, Pisanello A, Servadei F, Vaccaro S, Mukherjee P, Seyfried TN (2010) Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutr Metab (Lond) 7:33

    Article  Google Scholar 

  9. Champ CE, Palmer JD, Volek JS, Werner-Wasik M, Andrews DW, Evans JJ, Glass J, Kim L, Shi W (2014) Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol 117:125–131. doi:10.1007/s11060-014-1362-0

    Article  CAS  PubMed  Google Scholar 

  10. Chang HT, Olson LK, Schwartz KA (2013) Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: implication for ketogenic diet therapy. Nutr Metab (Lond) 10:47. doi:10.1186/1743-7075-10-47

    Article  CAS  Google Scholar 

  11. Nebeling LC, Miraldi F, Shurin SB, Lerner E (1995) Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr 14:202–208

    Article  CAS  Google Scholar 

  12. Rieger J, Bahr O, Maurer GD, Hattingen E, Franz K, Brucker D, Walenta S, Kammerer U, Coy JF, Weller M, Steinbach JP (2014) ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol 44:1843–1852. doi:10.3892/ijo.2014.2382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Seyfried TN, Kiebish MA, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P (2011) Metabolic management of brain cancer. Biochim Biophys Acta 1807:577–594

    Article  CAS  Google Scholar 

  14. Westman EC, Mavropoulos J, Yancy WS, Volek JS (2003) A review of low-carbohydrate ketogenic diets. Curr Atheroscler Rep 5:476–483

    Article  Google Scholar 

  15. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN (2007) The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 4:5

    Article  Google Scholar 

  16. Seyfried TN, Mukherjee P (2005) Targeting energy metabolism in brain cancer: review and hypothesis. Nutr Metab (Lond) 2:30

    Article  Google Scholar 

  17. Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P (2003) Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer 89:1375–1382. doi:10.1038/sj.bjc.6601269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Magee BA, Potezny N, Rofe AM, Conyers RA (1979) The inhibition of malignant cell growth by ketone bodies. Aust J Exp Biol Med Sci 57:529–539

    Article  CAS  Google Scholar 

  19. Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, Pizzo SV, Isaacs WB (2008) Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 68:11–19. doi:10.1002/pros.20683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, Kurniali PC, Hord NG, Noel M (2015) Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer & Metabol 3: 3 doi:10.1186/s40170-015-0129-1

    Article  Google Scholar 

  21. Laffel L (1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 15:412–426. doi:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8

    Article  CAS  PubMed  Google Scholar 

  22. Seymour KJ, Bluml S, Sutherling J, Sutherling W, Ross BD (1999) Identification of cerebral acetone by 1 H-MRS in patients with epilepsy controlled by ketogenic diet. MAGMA 8:33–42

    CAS  PubMed  Google Scholar 

  23. Gujar SK, Maheshwari S, Bjorkman-Burtscher I, Sundgren PC (2005) Magnetic resonance spectroscopy. J Neuroophthalmol 25:217–226

    Article  Google Scholar 

  24. Zarifi M, Tzika AA (2016) Proton MRS imaging in pediatric brain tumors. Pediatr Radiol 46:952–962. doi:10.1007/s00247-016-3547-5

    Article  PubMed  Google Scholar 

  25. Wilson M, Cummins CL, Macpherson L, Sun Y, Natarajan K, Grundy RG, Arvanitis TN, Kauppinen RA, Peet AC (2013) Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours. Eur J Cancer 49:457–464. doi:10.1016/j.ejca.2012.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Young GS (2007) Advanced MRI of adult brain tumors. Neurol Clin 25(947–973)

    Article  Google Scholar 

  27. Wootton-Gorges SL, Buonocore MH, Kuppermann N, Marcin J, Dicarlo J, Neely EK, Barnes PD, Glaser N (2005) Detection of cerebral {beta}-hydroxy butyrate, acetoacetate, and lactate on proton MR spectroscopy in children with diabetic ketoacidosis. AJNR Am J Neuroradiol 26:1286–1291

    PubMed  Google Scholar 

  28. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, DeGroot J, Wick W, Gilbert MR, Lassman AB (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972

    Article  Google Scholar 

  29. Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679

    Article  CAS  Google Scholar 

  30. Longo VD, Mattson MP (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181–192. doi:10.1016/j.cmet.2013.12.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Morris AA (2005) Cerebral ketone body metabolism. J Inherit Metab Dis 28:109–121. doi:10.1007/s10545-005-5518-0

    Article  CAS  PubMed  Google Scholar 

  32. Musa-Veloso K (2004) Non-invasive detection of ketosis and its application in refractory epilepsy. Prostaglandins, leukotrienes, and essential fatty acids 70: 329–335 doi:10.1016/j.plefa.2003.08.025

    Article  CAS  Google Scholar 

  33. Pan JW, Telang FW, Lee JH, de Graaf RA, Rothman DL, Stein DT, Hetherington HP (2001) Measurement of beta-hydroxybutyrate in acute hyperketonemia in human brain. J Neurochem 79:539–544

    Article  CAS  Google Scholar 

  34. Cecil KM, Mulkey SB, Ou X, Glasier CM (2015) Brain ketones detected by proton magnetic resonance spectroscopy in an infant with Ohtahara syndrome treated with ketogenic diet. Pediatr Radiol 45:133–137. doi:10.1007/s00247-014-3032-y

    Article  PubMed  Google Scholar 

  35. Zhou W, Mukherjee P, Kiebish KA, Mantis JG, Gorham KN, Mulrooney TJ, Markis WT, Seyfried TN (2006) KetoCal(R), a novel ketogenic diet therapy for brain cancer. Proc Amer Assoc. Cancer Res 47:3887

    Google Scholar 

  36. De Feyter HM, Behar KL, Rao JU, Madden-Hennessey K, Ip KL, Hyder F, Drewes LR, Geschwind JF, de Graaf RA, Rothman DL (2016) A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth. Neuro-oncol 18:1079–1087. doi:10.1093/neuonc/now088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Daikhin Y, Yudkoff M (1998) Ketone bodies and brain glutamate and GABA metabolism. Dev Neurosci 20:358–364 pii]

    Article  CAS  Google Scholar 

  38. Bluml S, Shic F, Lai L, Yahya K, Lin A, Ross B (2002) Glutamate-glutamine cycling in epileptic patients on ketogenic diets. International Society for Magnetic Resonance in Medicine. Hawaii

    Google Scholar 

  39. Horská A, Barker PB (2010) Imaging of brain tumors: MR spectroscopy and metabolic imaging. Neuroimaging Clin of North Am 20: 293–310

    Article  Google Scholar 

  40. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clini Oncol 28:1963–1972. doi:10.1200/JCO.2009.26.3541

    Article  Google Scholar 

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Acknowledgements

To Vicki Myers for editorial assistance.

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    Authors and Affiliations

    1. Functional Brain Center, The Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv, 64239, Israel

      Moran Artzi, Gilad Liberman, Faina Vitinshtein, Orna Aizenstein & Dafna Ben Bashat

    2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

      Moran Artzi & Dafna Ben Bashat

    3. Gonda Multidisciplinary Brain Res. Center, Bar Ilan University, Ramat Gan, Israel

      Gilad Liberman

    4. Unit of Clinical Nutrition, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

      Nachum Vaisman

    5. Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

      Felix Bokstein

    6. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

      Dafna Ben Bashat

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    1. Moran Artzi
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    Correspondence to Dafna Ben Bashat.

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    There is no conflict of interest associated with the publication of this paper on the part of any of the authors.

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    Moran Artzi and Gilad Liberman equally contributed to this study.

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    Artzi, M., Liberman, G., Vaisman, N. et al. Changes in cerebral metabolism during ketogenic diet in patients with primary brain tumors: 1H-MRS study. J Neurooncol 132, 267–275 (2017). https://doi.org/10.1007/s11060-016-2364-x

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    • DOI: https://doi.org/10.1007/s11060-016-2364-x

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