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Ketogenic Diet in Neurodegenerative Diseases

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Ketosis. It has become one of the most popular words of the 21st century. Often connected to weight loss plans, “ketosis” is also strongly associated with epilepsy: the ketogenic diet was first introduced by clinicians as a treatment for epilepsy in the 1920s. Over the last decade, researchers have been studying the effect of ketosis on other neurological and mitochondrial disorders, with promising results.

In ketosis, the mitochondria burn fat instead of glucose for energy metabolism. Ketosis can be achieved through periods of fasting or by restricting the intake of carbohydrates in the diet, leading the body to break down fatty acids to produce higher-than-normal levels of the so-called ketone bodies—acetoacetate, β-hydroxybutyric acid, and acetone—through a process called ketogenesis, which occurs principally in the mitochondrial matrix in the liver.1 The “state of ketosis” has been shown to exert a protective action against neurological diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and more.2-4 In AD and PD, human studies have shown a reduction of disease symptoms in participants following a ketogenic diet.5

A therapeutic ketogenic diet has been studied by IFM educator Terry Wahls, MD, IFMCP with the specific aim of reversing the symptoms of multiple sclerosis (MS). Such diets have been shown to stimulate mitochondrial biogenesis, improve mitochondrial function, and reduce oxidative stress.2,3,6,7 Dr. Wahls has used ketogenic diets in her clinical practice for a wide variety of health issues that result from mitochondrial disease. In the following IFM video, Dr. Wahls talks about the importance of diet for patients with neurological disease symptoms like fatigue.

(Video Time: 2 minutes) Terry Wahls, MD, is a clinical professor of medicine at the University of Iowa, where she teaches internal medicine residents, sees patients in a therapeutic lifestyle clinic, and conducts clinical trials. Dr. Wahls is a patient with secondary progressive multiple sclerosis. She restored her health using a diet and lifestyle program she designed specifically for her brain.

Neuroprotection & Ketogenic Therapies

In 2004, the first randomized controlled trial of the ketogenic diet with medium-chain triglycerides in humans with AD or mild cognitive impairment (MCI) showed that higher ketone values were associated with greater improvement in paragraph recall.8 Subsequent studies have demonstrated that ketone bodies act as neuroprotective agents by raising ATP levels and reducing the production of reactive oxygen species in neurological tissues, together with mitochondrial biogenesis, which may help to enhance the regulation of synaptic function.1,6 Caloric restriction, in and of itself, has also been suggested to exert neuroprotective effects, including improved mitochondrial function, decreased oxidative stress and apoptosis, and inhibition of pro-inflammatory mediators such as the cytokines tumor necrosis factor-α and inflammatory interleukins.1

In a 2017 Ketogenic Diet Retention and Feasibility Trial, 15 patients with AD were put on a medium-chain triglyceride–supplemented ketogenic diet: approximately 70% of energy as fat, including the MCT, 20% of energy as protein, and less than 10% of energy as carbohydrates. Researchers observed that in a state of ketosis, the mean score on the Alzheimer’s Disease Assessment Scale cognitive subscale improved significantly during the diet and reverted to baseline after the washout.9

Results from a 2020 systematic review of 10 randomized controlled trials indicated that among adults with MCI and/or AD, adherence to an acute or long-term (45-180 days) ketogenic therapy (ketogenic diet, MCT-based, or ketogenic formulas/meals) improved both acute and long-term cognition.10 Specifically, one of the reviewed studies from 2019 examined the effect of an MCT–based ketogenic diet on the cognitive function of 20 Japanese patients with mild-to-moderate AD.11 At eight weeks, the patients showed significant improvement in their immediate and delayed logical memory tests, and at 12 weeks, they showed significant improvements in a digit-symbol coding test and immediate logical memory test, tests which evaluate verbal memory and cognitive processing speed.11

A study of 150 migraine patients found that the ketogenic diet may be a rapid-onset effective prophylaxis for both episodic and chronic migraine.12 Researchers speculate that the ketogenic diet restores brain excitability and metabolism to counteract neuroinflammation in migraine patients.2 Although the ketogenic diet is seen by many as a promising therapy for diverse neurological diseases, the long-term effects of this kind of diet in humans remains uncertain.2

To this end, some researchers have begun to study the effects of intermittent metabolic switching (IMS).13,14 This entails repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting, and sleeping), which may optimize brain function and resilience throughout the lifespan.13 This metabolic switching may impact multiple signaling pathways that promote neuroplasticity and resistance of the brain to injury and disease.13 Although IMS may enhance brain function and stress resistance, the research is still new and seen mainly in animal models. The question of what specific IMS regimen(s) is ideal for brain health throughout the life course is also unknown.13

Future research should help us better understand how ketogenic therapies work and what effects they have on mitochondrial function and neurological disorders. Ketogenic diets may prove to be another tool functional medicine clinicians can use to help improve outcomes for patients with neurodegenerative disorders. To learn more, visit IFM’s Bioenergetics Advanced Practice Module (APM).

Learn More About Mitochondrial Function

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References

  1. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013;67(8):789-796. doi:10.1038/ejcn.2013.116
  2. Paoli A, Bianco A, Damiani E, Bosco G. Ketogenic diet in neuromuscular and neurodegenerative diseases. Biomed Res Int. 2014;2014:474296. doi:10.1155/2014/474296
  3. Branco AF, Ferreria A, Simões RF, et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Invest. 2016;46(3):285-298. doi:10.1111/eci.12591
  4. Pavón S, Lázaro E, Martínez O, et al. Ketogenic diet and cognition in neurological diseases: a systematic review. Nutr Rev. 2021;79(7):802-813. doi:10.1093/nutrit/nuaa113
  5. Wlodarek D. Role of ketogenic diets in neurodegenerative diseases (Alzheimer’s disease and Parkinson’s disease). Nutrients. 2019;11(1):E169. doi:10.3390/nu11010169
  6. Yang H, Shan W, Zhu F, Wu J, Wang Q. Ketone bodies in neurological diseases: focus on neuroprotection and underlying mechanisms. Front Neurol. 2019;10:585. doi:10.3389/fneur.2019.00585
  7. Brocchi A, Rebelos E, Dardano A, Mantuano M, Daniele G. Effects of intermittent fasting on brain metabolism. Nutrients. 2022;14(6):1275. doi:10.3390/nu14061275
  8. Reger MA, Henderson ST, Hale C, et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 2004;25(3):311-314. doi:10.1016/S0197-4580(03)00087-3
  9. Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimer’s Dement. 2017;4:28-36. doi:10.1016/j.trci.2017.11.002
  10.  Grammatikopoulou MG, Goulis DG, Gkiouras K, et al. To keto or not to keto? A systematic review of randomized controlled trials assessing the effects of ketogenic therapy on Alzheimer disease. Adv Nutr. 2020;11(6):1583-1602. doi:10.1093/advances/nmaa073
  11.  Ota M, Matsuo J, Ishida I, et al. Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function in patients with mild-to-moderate Alzheimer’s disease. Neurosci Lett. 2019;690:232-236. doi:10.1016/j.neulet.2018.10.048
  12.  Barbanti P, Fofi L, Aurilia C, Egeo G, Caprio M. Ketogenic diet in migraine: rationale, findings and perspectives. Neurol Sci. 2017;38(Suppl 1):111-115. doi:10.1007/s10072-017-2889-6
  13.  Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, neuroplasticity, and brain health. Nat Rev Neurosci. 2018;19(2):63-80. doi:10.1038/nrn.2017.156
  14.  Mishra S, Singh B. Intermittent fasting and metabolic switching: a brief overview. Biomed Pharmacol J. 2020;13(3). doi:10.13005/bpj/2030

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