Top

Published in:

Open Access 01-12-2024 | Parkinson's Disease | Research

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease

Authors: Alexander H. Choi, Melanie Delgado, Kong Y. Chen, Stephanie T. Chung, Amber Courville, Sara A. Turner, Shanna Yang, Kayla Airaghi, Irene Dustin, Patrick McGurrin, Tianxia Wu, Mark Hallett, Debra J. Ehrlich

Published in: BMC Neurology | Issue 1/2024

Abstract

Background

A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson’s disease (PD).

Objective

Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG).

Methods

A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson’s Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity.

Results

A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups.

Conclusions

An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease.

Trial Registration

Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 – Sept 13, 2022.

Available only for authorised users

Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021;7:47. https://doi.org/10.1038/s41572-021-00280-3.CrossRefPubMed

Perier C, Vila M. Mitochondrial Biology and Parkinson’s Disease. Cold Spring Harb Perspect Med. 2012;2:a009332–a009332.PubMedPubMedCentralCrossRef

Abeti R, Abramov AY. Mitochondrial Ca2+ in neurodegenerative disorders. Pharmacol Res. 2015;99:377–81.PubMedCrossRef

Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Front Neuroanat. 2015;9:91.

Angelova PR, Abramov AY. Functional role of mitochondrial reactive oxygen species in physiology. Free Radical Biol Med. 2016;100:81–5.CrossRef

Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, et al. PGC-1, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease. Sci Transl Med. 2010;2:52ra73.PubMedPubMedCentralCrossRef

Sulzer D, Surmeier DJ. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Mov Disord. 2013;28:715–24. https://doi.org/10.1002/mds.25187.CrossRefPubMed

Craft S, Asthana S, Newcomer JW, Wilkinson CW, Matos IT, Baker LD, et al. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry. 1999;56:1135–40. https://doi.org/10.1001/archpsyc.56.12.1135.CrossRefPubMed

Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids. 2004;70:309–19.PubMedCrossRef

10.

Veech RL, Bradshaw PC, Clarke K, Curtis W, Pawlosky R, King MT. Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life. 2017;69:305–14.PubMedCrossRef

11.

Cullingford TE. The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders. Prostaglandins Leukot Essent Fatty Acids. 2004;70:253–64.PubMedCrossRef

12.

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

13.

Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol (Lausanne). 2014;5:161. https://doi.org/10.3389/fendo.2014.00161.CrossRefPubMed

14.

Dunn L, Allen GF, Mamais A, Ling H, Li A, Duberley KE, et al. Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease. Neurobiol Aging. 2014;35:1111–5. https://doi.org/10.1016/j.neurobiolaging.2013.11.001.CrossRefPubMedPubMedCentral

15.

Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25:42–52. https://doi.org/10.1016/j.tem.2013.09.002.CrossRefPubMed

16.

Greco T, Glenn TC, Hovda DA, Prins ML. Ketogenic diet decreases oxidative stress and improves mitochondrial respiratory complex activity. J Cereb Blood Flow Metab. 2016;36:1603–13.PubMedCrossRef

17.

Miller, V.J., Villamena, F.A., and Volek, J.S. Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. J Nutr Metab. 2018; 5157645. https://doi.org/10.1155/2018/5157645.

18.

Nagpal R, Neth BJ, Wang SH, Craft S, Yadav H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer’s disease markers in subjects with mild cognitive impairment. EBioMedicine. 2019;47:529–42.PubMedPubMedCentralCrossRef

19.

Mujica-Parodi LR, Amgalan A, Sultan SF, Antal B, Sun X, Skiena S, Lithen A, Adra N, Ratai E-M, Weistuch C, Govindarajan ST, Strey HH, Dill KA, Stufflebeam SM, Veech RL, Clarke K. Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proc Natl Acad Sci. 2020;117:6170–7.PubMedPubMedCentralCrossRef

20.

Avgerinos KI, Egan JM, Mattson MP, Kapogiannis D. Medium Chain Triglycerides induce mild ketosis and may improve cognition in Alzheimer’s disease. A systematic review and meta-analysis of human studies. Aging Res Rev. 2020;58:101001.CrossRef

21.

Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, Chance B, Clarke K, Veech RL. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651–8.PubMedCrossRef

22.

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-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest. 2003;112:892–901.PubMedPubMedCentralCrossRef

23.

Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–9. https://doi.org/10.1038/nm.3804.CrossRefPubMedPubMedCentral

24.

Shaafi S, Najmi S, Aliasgharpour H, Mahmoudi J, Sadigh-Etemad S, Farhoudi M, Baniasadi N. The efficacy of the ketogenic diet on motor functions in Parkinson’s disease: A rat model. Iran J Neurol. 2016;15:63–9.PubMedPubMedCentral

25.

Vanitallie TB, Nonas C, Di Rocco A, Boyar K, Hyams K, Heymsfield SB. Treatment of Parkinson disease with diet-induced hyperketonemia: a feasibility study. Neurology. 2005;64:728–30. https://doi.org/10.1212/01.WNL.0000152046.11390.45.CrossRefPubMed

26.

Phillips MCL, Murtagh DKJ, Gilbertson LJ, Asztely FJS, Lynch CDP. Low-fat versus ketogenic diet in Parkinson’s disease: A pilot randomized controlled trial. Mov Disord. 2018;33:1306–14.PubMedPubMedCentralCrossRef

27.

Krikorian R, Shidler MD, Summer SS, Sullivan PG, Duker AP, Isaacson RS, Espay AJ. Nutritional ketosis for mild cognitive impairment in Parkinson’s disease: A controlled pilot trial. Clinical Parkinsonism & Related Disorders. 2019;1:41–7.CrossRef

28.

Harvey CJDC, Schofield GM, Williden M, McQuillan JA. The Effect of Medium Chain Triglycerides on Time to Nutritional Ketosis and Symptoms of Keto-Induction in Healthy Adults: A Randomized Controlled Clinical Trial. J Nutr Metab. 2018;2018:2630565.CrossRef

29.

Anderson JC, Mattar SG, Greenway FL, Lindquist RJ. Measuring ketone bodies for the monitoring of pathologic and therapeutic ketosis. Obes Sci Pract. 2021;2021(7):646–56. https://doi.org/10.1002/osp4.516.CrossRef

30.

Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 2013;36:32–40. https://doi.org/10.1016/j.tins.2012.11.005.CrossRefPubMed

31.

de Hemptinne C, Ryapolova-Webb ES, Air EL, Garcia PA, Miller KJ, Ojemann JG, et al. Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease. Proc Natl Acad Sci U S A. 2013;110:4780–5. https://doi.org/10.1073/pnas.1214546110.CrossRefPubMedPubMedCentral

32.

Gayoso-Diz P, Otero-Gonzalez A, Rodriguez-Alvarez MX, Gude F, Garcia F, De Francisco A, et al. Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age: EPIRCE cross-sectional study. BMC Endocr Disord. 2013;13:47. https://doi.org/10.1186/1472-6823-13-47.CrossRefPubMedPubMedCentral

33.

ClinicalTrials.gov database. https://clinicaltrials.gov/ct2/show/results/NCT04584346. Accessed 12 May 2023.

34.

Weir JB. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1949;1949(109):1–9. https://doi.org/10.1113/jphysiol.1949.sp004363.CrossRef

35.

Wiers CE, Vendruscolo LF, van der Veen JW, Manza P, Shokri-Kojori E, Kroll DS, et al. Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents. Sci Adv. 2021;7:eabf6780.PubMedPubMedCentralCrossRef

36.

Stoet G. PsyToolkit - A software package for programming psychological experiments using Linux. Behav Res Methods. 2010;42:1096–104.PubMedCrossRef

37.

Stoet, G. PsyToolkit: A novel web-based method for running online questionnaires and reaction-time experiments. Teach. Psychol. 2017;44:24-31.

38.

Baumgartner RN, Chumlea WC, Roche AF. Bioelectric impedance for body composition. Exerc Sport Sci Rev. 1990;18:193–224.PubMedCrossRef

39.

Bosy-Westphal A, Schautz B, Later W, Kehayias JJ, Gallagher D, Muller MJ. What makes a BIA equation unique? Validity of eight-electrode multifrequency BIA to estimate body composition in a healthy adult population. Euro Jnl Clin Nutr. 2013;67:S14–21.CrossRef

40.

Choi YJ, Jeon SM, Shin S. Impact of a Ketogenic Diet on Metabolic Parameters in Patients with Obesity or Overweight and with or without Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Nutrients. 2020;12:2005.PubMedPubMedCentralCrossRef

41.

Hall KD, Bemis T, Brychta R, Chen KY, Courville A, Crayner EJ, et al. Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity. Cell Metab. 2015;22:427–36.PubMedPubMedCentralCrossRef

42.

Cantello R, Varrasi C, Tarletti R, Cecchin M, D’Andrea F, Veggiotti P, et al. Ketogenic diet: electrophysiological effects on the normal human cortex. Epilepsia. 2007;48:1756–63.PubMedCrossRef

43.

Stam CJ, Tewarie P, Van Dellen E, van Straaten EC, Hillebrand A, Van Mieghem P. The trees and the forest: Characterization of complex brain networks with minimum spanning trees. Int J Psychophysio. 2014;92:129–38.CrossRef

44.

Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, et al. The metric properties of a novel nonmotor symptoms scale for Parkinson’s disease: Results from an international pilot study. Mov Disord. 2007;22:1901–11.PubMedCrossRef

45.

Kenna JE, Bakeberg MC, Gorecki AM, Yen Tay AC, Winter S, Mastaglia FL, Anderton RS. Characterization of Gastrointestinal Symptom Type and Severity in Parkinson’s Disease: A Case-Control Study in an Australian Cohort. Mov Disord Clin Pract. 2021;8:245–53.PubMedPubMedCentralCrossRef

46.

International Foundation for Gastrointestinal Disorders. 147-Personal Daily Diary (IBS). https://iffgd.org/resources/publication-library/personal-daily-diary-ibs/. Accessed 9 October 2023.

47.

Foreman KB, Addison O, Kim HS, Dibble LE. Testing balance and fall risk in persons with Parkinson disease, an argument for ecologically valid testing. Parkinsonism Relat Disord. 2011;17:166–71.PubMedPubMedCentralCrossRef

48.

Hofheinz M, Schusterschitz C. Dual task interference in estimating the risk of falls and measuring change: a comparative, psychometric study of four measurements. Clin Rehabil. 2010;24:831–42.PubMedCrossRef

49.

Dal Bello-Haas V, Klassen L, Sheppard MS, Metcalfe A. Psychometric Properties of Activity, Self-Efficacy, and Quality-of-Life Measures in Individuals with Parkinson Disease. Physiother Can. 2011;63:47–57.CrossRef

50.

Huang SL, Hsieh CL, Wu RM, Tai CH, Lin CH, Lu WS. Minimal detectable change of the timed “up & go” test and the dynamic gait index in people with Parkinson disease. Phys Ther. 2011;91:114–21.PubMedCrossRef

51.

Nocera JR, Stegemoller EL, Malaty IA, Okun MS, Marsiske M, Hass CJ. National Parkinson Foundation Quality Improvement Initiative Investigators. Using the Timed Up & Go test in a clinical setting to predict falling in Parkinson’s disease. Arch Phys Med Rehabil. 2013;94:1300–5.PubMedPubMedCentralCrossRef

52.

Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT. Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;2010(2010):18.CrossRef

53.

Pan JW, Rothman TL, Behar KL, Stein DT, Hetherington HP. Human brain beta-hydroxybutyrate and lactate increase in fasting-induced ketosis. J Cereb Blood Flow Metab. 2000;20:1502–7. https://doi.org/10.1097/00004647-200010000-00012.CrossRefPubMed

54.

Johansson ME, Cameron IGM, Van der Kolk NM, de Vries NM, Klimars E, Toni I, Bloem BR, Helmich RC. Aerobic Exercise Alters Brain Function and Structure in Parkinson’s Disease: A Randomized Controlled Trial. Ann Neurol. 2022;91:203–16.PubMedPubMedCentralCrossRef

55.

Maini Rekdal V, Bess EN, Bisanz JE, Turnbaugh PJ, Balskus EP. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science. 2019;364(6445):eaau6323.PubMedCrossRef

56.

Asnicar F, Berry SE, Valdes AM, Nguyen LH, Piccinno G, Drew DA, et al. Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals. Nat Med. 2021;27:321–32.PubMedPubMedCentralCrossRef

57.

Gershuni VM, Yan SL, Medici V. Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome. Curr Nutr Rep. 2018;7:97–106.PubMedPubMedCentralCrossRef

58.

Yuan X, Wang J, Yang S, Gao M, Cao L, Li X, Hong D, Tian S, Sun C. Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis. Nutr Diabetes. 2020;10:38.PubMedPubMedCentralCrossRef

59.

Sultani R, Tong DC, Peverelle M, Lee YS, Baradi A, Wilson AM. Elevated Triglycerides to High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio Predicts Long-Term Mortality in High-Risk Patients. Heart Lung Circ. 2020;2020(29):414–21. https://doi.org/10.1016/j.hlc.2019.03.019.CrossRef

60.

Masood, W., Annamaraju, P., Khan Suheb, M. Z., & Uppaluri, K. R. Ketogenic Diet. In: StatPearls. 2023. https://www.ncbi.nlm.nih.gov/books/NBK499830/. Accessed 7 Sept 2023.

61.

Femat-Roldán G, Gaitán Palau MA, Castilla-Cortázar I, Elizondo Ochoa G, Moreno NG, Martín-Estal I, Jiménez Yarza M. Altered Body Composition and Increased Resting Metabolic Rate Associated with the Postural Instability/Gait Difficulty Parkinson’s Disease Subtype. Parkinson’s disease. 2020;2020:8060259.PubMedPubMedCentralCrossRef

62.

Brooks PL, Peever JH. Impaired GABA and glycine transmission triggers cardinal features of rapid eye movement sleep behavior disorder in mice. J Neurosci. 2011;31:7111–21.PubMedPubMedCentralCrossRef

63.

He R, Yan X, Guo J, Xu Q, Tang B, Sun Q. Recent Advances in Biomarkers for Parkinson’s Disease. Front Aging Neurosci. 2018;10:305. https://doi.org/10.3389/fnagi.2018.00305.CrossRefPubMedPubMedCentral

64.

Rahmani M, Rahmani F, Rezaei N. The Brain-Derived Neurotrophic Factor: Missing Link Between Sleep Deprivation, Insomnia, and Depression. Neurochem Res. 2020;45:221–31. https://doi.org/10.1007/s11064-019-02914-1.CrossRefPubMed

65.

Gyorkos A, Baker MH, Miutz LN, Lown DA, Jones MA, Houghton-Rahrig LD. Carbohydrate-restricted Diet and Exercise Increase Brain-derived Neurotrophic Factor and Cognitive Function: A Randomized Crossover Trial. Cureus. 2019;11:e5604.PubMedPubMedCentral

Title: A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease
Authors: Alexander H. Choi
Melanie Delgado
Kong Y. Chen
Stephanie T. Chung
Amber Courville
Sara A. Turner
Shanna Yang
Kayla Airaghi
Irene Dustin
Patrick McGurrin
Tianxia Wu
Mark Hallett
Debra J. Ehrlich
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Parkinson's Disease
Published in: BMC Neurology / Issue 1/2024
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-024-03603-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease

Abstract

Background

Objective

Methods

Results

Conclusions

Trial Registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusions

Trial Registration

Please log in to get access to this content

Other articles of this Issue 1/2024

The impact of stress hyperglycemia ratio on short-term and long-term outcomes for acute basilar artery occlusion underwent endovascular treatment

Cognitive function and quantitative electroencephalogram analysis in subjects recovered from COVID-19 infection

Partial facial paralysis induced by sialolithiasis of the parotid gland: a case report

MRI-based clinical-radiomics nomogram to predict early neurological deterioration in isolated acute pontine infarction: a two-center study in Northeast China

Genetic heterogeneity in epilepsy and comorbidities: insights from Pakistani families

Association between serum triglycerides and stroke type, severity, and prognosis. Analysis in 6558 patients