Proton MRS monitoring of Atkins-based dietary therapy in patients with glioma
Peter B Barker1,2, Subechhya Pradhan1, Yanqin Lin1,3, Karisa C Schreck4, Doris D.M. Lin1, Jaishri Blakeley4,5, and Roy E Strowd5,6

1Radiology, Johns Hopkins Univ School of Medicine, Baltimore, MD, United States, 2F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, 3Department of Electronic Science, Xiamen University, Xiamen, China, People's Republic of, 4Neurology, Johns Hopkins Univ School of Medicine, Baltimore, MD, United States, 5Oncology, Johns Hopkins Univ School of Medicine, Baltimore, MD, United States, 6Department of Neurology and Internal Medicine, Wake Forest School of Medicine, Winston Salem, NC, United States

Synopsis

5 patients with high grade glioma were enrolled in an 8-week dietary therapy program based on the modified Atkin’s diet. Tumor and contralateral brain metabolism was monitored before and after therapy using proton MRS. Significant reductions in contralateral NAA were observed post treatment, as well as increases in acetone in both lesion and contralateral brain. MRS may be useful for monitoring the efficacy of dietary therapy in patients with malignant glioma.

Introduction

Malignant gliomas are known to have a high glycolytic rate, and are dependent on glucose for energy metabolism (the “Warburg effect”). In animal models of glioma, reduced glucose levels via calorie restriction have been associated with reductions in tumor growth and improved survival(1). Ketogenic diets (KDs) are high-fat, low-carbohydrate dietary interventions which reduce serum glucose, induce systemic ketosis, shift energy metabolism to ketone bodies, and have been explored in recurrent glioblastoma(2,3). The modified Atkins diet is a novel KD alternative which has proven efficacious in the management of refractory epilepsy and has been explored in glioma (2).The purpose of this pilot study was to evaluate the feasibility of an 8-week Glioma modified Atkins-based Diet (GLAD), and to explore the biologic activity in both tumor and normal brain regions using proton MR spectroscopy (MRS).

Methods

5 patients with biopsy-confirmed high grade glioma (2F, age 40±6 yrs) who were post-surgery and more than 7 months post-chemoradiation were evaluated by MRI/MRS at baseline and after 8 weeks of GLAD. GLAD consisted of 2 ‘fasting’ days (caloric restriction to 20% of recommended daily allowance,) interleaved between 5 days following the modified-Atkins diet (carbohydrate intake restricted to 20 gm) each week. MRS was performed at 3T in both the lesion and in a mirror voxel in the contralateral hemisphere (Philips 3T Achieva, 32-channel head coil, sLASER localization, TR/TE 2.2s/34ms, 2nd order shimming, VAPOR water suppression, 2x2x2cm, 128 averages, 5 min scan time). Voxel placement was in a region of the lesion with T2 hyperintensity on MRI, adjacent to the resection cavity, considered by a radiologist to be most likely consistent with residual tumor. Data were analyzed using the ‘LCModel’ program using a basis set consisting of acetone (Ace), beta-hydroxybutyrate (bHb), acetoacetate (AcAc), 2-hydroxyglutarate (2-HG) and citrate (Cit) in addition to a standard set of metabolites, lipid and macromolecule resonances found in normal brain. Concentrations were expressed relative to the brain water signal (i.u), as well as ratios to total creatine (tCr).

Results

All patients tolerated GLAD and all achieved measurable ketosis. Spectra and images at 8 weeks in one case are shown in figure 1. Figure 2 shows selected brain metabolite and ketone concentrations at baseline and at 8 weeks. As expected, multiple compounds were different between lesion and normal brain (e.g. at baseline, Glx p<0.02, tNAA p<0.001, tCr, p<0.02, Lac p < 0.04 (2nd visit only)). The only significant difference in metabolite concentrations between baseline and 8 week follow-up was a decrease in tNAA in the contralateral hemisphere(visit 1 [tNAA]=7.29±0.41, visit 2 [tNAA]= 6.89±0.41, p<0.02 (paired t-test)). Of the ketone bodies (Ace, AcAc, bHb), none were detectable by MRS at baseline, however acetone was reliably determined by LCModel at 8 weeks in both lesion ([Ace]=0.41±0.34 i.u., mean CRLB=47%) and normal brain ([Ace]=0.49±0.23 i.u., mean CRLB=28%). In the lesion, MRS was suggestive of stable disease in the cohort as a whole, since no significant differences in tumor markers such as tCho (or other compounds, e.g. tNAA or mI) were observed.

Discussion

Preliminary results of this pilot study demonstrate the ability of brain MRS to monitor the metabolic consequences of dietary interventions in patients with high grade glioma. Consistent with a prior report of MRS in KD (in patients with epilepsy (4)), increases in detectable acetone signal were observed both in lesional and normal brain. The lack of overall changes in tumor markers (such as Cho) is consistent with the clinical stability and lack of progression seen on brain MRI at 8 weeks in 4 of the 5 cases. The origin of the decline in tNAA in the contralateral hemisphere is unclear; possible explanations might include reduced NAA production, since NAA is synthesized in neuronal mitochondria closely related to the TCA cycle, whose flux may be reduced under ketotic conditions, or perhaps a delayed effect of the prior chemoradiation on neuronal health. Future studies of GLAD therapeutic efficacy will require both a larger sample size, and the inclusion of a placebo group for comparison.

Acknowledgements

We would like to thank and acknowledge Ms. Elaine Freeman on behalf of Dr. and Mrs. John Freeman and Dr. Robert and Mrs. Margaret Martz for their financial and ongoing support of this study

Yanqin Lin is grateful to the China Scholarship Council for a fellowship.

References

1. Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer 2003;89(7):1375-1382.

2. Strowd R, Cervenka M, Henry B, Kossoff E, Hartman A, Blakeley J. Glycemic modulation in neuro-oncology: experience and future directions using a modified Atkins diet for high-grade brain tumors. . Neuro-Oncology Pract 2015:1-10.

3. Rieger J, Bahr O, Maurer GD, Hattingen E, Franz K, Brucker D, Walenta S, Kammerer U, Coy JF, Weller M, Steinbach JP. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol 2014;44(6):1843-1852.

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

Figures

Example of one case at 8-weeks, T2-weighted MRI indicating voxel locations, lesion and contralateral hemisphere spectral outputs from the ‘LCModel’ software.

Metabolite concentrations (i.u.) in the lesion and contralateral hemisphere, at baseline and at 8 weeks. Significantly different values are indicated in blue (lesion vs. contralateral, at either time point) and red (baseline vs. 8-weeks).



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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