Neuroprotective Effects of the Ketogenic Diet (Part 3: Specific Conditions)

by Milene Brownlow, PhD

This 3-part blog series explores the history (Part 1), mechanisms and evidence (Part 2) underlying the neuroprotective effects of the ketogenic diet. In the final part 3, let’s investigate the current scientific evidence in support of the ketogenic diet (KD) as a therapeutic approach for specific neurological disorders.

Preclinical study evidence

In rodents, diet-induced ketosis has been shown to reverse motor deficits in a model of amyotrophic lateral sclerosis (ALS),¹ reduce lesion volume after traumatic brain injury (TBI),² improve pathology and behavioral performance in Alzheimer’s disease (AD) transgenic model,³ and attenuate stress-induced deficits in behavioral performance and hippocampal brain-derived neurotrophic factor (necessary for synaptic plasticity) levels in adult rats.⁴ Addition of beta-hydroxybutyrate (bHB) to cell cultures prevented neuronal death following exposure to toxins associated with AD and Parkinson’s disease (PD).⁵ However, the large variability in experimental design (diet composition, model used, treatment duration, age at the start of study) highlights the challenges associated with the translatability of preclinical models and the importance of human clinical trials.

KD interventions in patients with cognitive decline

So far relatively few human trials have been conducted leveraging the use of ketogenic medium-chain triglycerides (MCT) in patients with mild-to-moderate AD.^6-9 Despite differences in study design, researchers observed that improved cognitive outcomes were:

• Positively correlated with the level of ketosis^{6-7, 9}
• Associated with duration in ketosis (performance returned to baseline levels following washout period)⁹
• More pronounced in patients who are ApoE4 negative (genetic isoform of the apolipoprotein E that confers increased risk for developing AD)^{6-8, 10}
• Also observed in elderly, non-demented subjects¹¹

Moreover, in an era of increasing need for individualized approaches, case studies demonstrate:

• Oral administration of a ketone monoester for 20 months improved mood, affect, and cognitive ability in a patient with advanced AD¹²
• Personalized ketogenic protocols with lifestyle modifications such as physical exercise and brain training resulted in better cognitive scores in patients with comorbid cognitive impairment and metabolic syndrome^13-14

Other neurological conditions & emerging science

The neuroprotective properties associated with decreased inflammation, oxidative stress, and improved mitochondrial bioenergetics also render ketogenic approaches a promising metabolic therapy for several other neurological disorders, such as:

• TBI and stroke: Ketosis has been associated with higher tolerance to hypoxic environments and neuroprotection following TBI, stroke, and ischemia-induced brain edema; however, these conditions require early delivery of ketones to maximize therapeutic effectiveness, and an optimal therapeutic window is still unclear.²
• Diet- or fasting-induced ketosis in patients with brain tumors: Some cancer cells are highly dependent on glucose. Carbohydrate restriction has been shown to result in smaller tumors with better-defined borders, facilitating surgical resection and decreasing chemotherapy side effects.¹⁵
• Enhancing motor function in neuromuscular diseases such as PD¹⁶ and ALS¹ and attenuating brain inflammation and oxidative stress in a mouse model of MS¹⁷
• Autism Spectrum Disorders (ASD): Recent studies have implicated mitochondrial dysfunction in ASD, characterized by behavioral deficits in sociability and communication and clinical manifestations may include seizures and sleep disturbances.¹⁸
• Chronic cluster headaches (CCH): A small 12-week clinical study implementing a ketogenic diet resulted in significant reduction in average CCH attacks, and in responders, the majority experienced full resolution of CCH,¹⁹ which is considered the most severe type of headache
• Migraines: Although the precise mechanisms are unclear, ketosis may provide migraine relief via modulation of brain excitability and energetic metabolism, in addition to decreased neuroinflammation and oxidative stress²⁰
• While KD-induced benefits are explored in the context of neurological disorders, a few research groups are investigating its potential for cognitive augmentation in healthy subjects with modest, yet encouraging results^4,21

Overall, relatively few human trials have been completed so far. However, numerous clinical and proof-of-concept studies are underway and will likely contribute to the greater clinical acceptance and adaptation of ketogenic programs to better suit different patients and conditions.

When it comes to neurodegenerative disorders, the underlying brain pathology starts developing decades before the appearance of clinical symptoms. Consequently, by the time a patient is diagnosed, the disease is well-established and more challenging to revert. As a result, prevention and early diagnosis remain the best approaches to improve the quality of life of patients, caregivers, and loved ones.

 Citations

1. Zhao W et al. 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. 2012;7(11):349191.
2. Prins ML et al. The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J Lipid Res. 2014;55(12):2450-7.
3. Van der Auwera I et al. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer’s disease. Nutr Metab. 2005;2:28.
4. Brownlow ML et al. Nutritional ketosis affects metabolism and behavior in Sprague-Dawley rats in both control and chronic stress environments. Front Mol Neurosci. 2017;10:129.
5. Kashiwaya Y et al. D-β-Hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci USA. 2000;97(10):5440-4.
6. Reger MA et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 2004;25(3):311-4.
7. Henderson ST et al. 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). 2009;6:31.
8. Ohnuma T et al. Benefits of use, and tolerance of, medium-chain triglyceride medical food in the management of Japanese patients with Alzheimer’s disease: a prospective, open-label pilot study. Clin Interv Aging. 2016;11:29-36.
9. Taylor MK et al. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement. 2017;4:28-36.
10. Rebello CJ et al. Pilot feasibility and safety study examining the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment: A randomized controlled trial. BBA Clin. 2015;3:123-5.
11. Ota M et al. Effect of a ketogenic meal on cognitive function in elderly adults: potential for cognitive enhancement. Psychopharmacology (Berl). 2016;233(21-22):3797-3802.
12. Newport MT et al. A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer’s disease. Alzheimer’s Dement. 2015;11(1):99-103.
13. Dahlgren K et al. Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of mild cognitive impairment: A case study. Diabetes Metab Syndr. 2018;pii:S1871-4021(18)30116-4.
14. Brown D et al. Metabolic syndrome marks early risk for cognitive decline with APOE4 gene variation: A case study. Diabetes Metab Syndr. 2018;pii:S1871-4012(18)30115-2.
15. Poff A et al. Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma. Semin Cancer Biol. 2017;pii:S1044-578X(17)30124-4.
16. Paoli A et al. Ketogenic diet in neuromuscular and neurodegenerative diseases. Biomed Res Int. 2014;2014:474296.
17. Kim DY et al. Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis. PLoS One. 2012;7(5):e35476.
18. Cheng N et al. Metabolic dysfunction underlying Autism Spectrum Disorder and potential treatment approaches. Front Mol Neurosc. 2017;10:34.
19. Di Lorenzo C et al. Efficacy of modified Atkins ketogenic diet in chronic cluster headache: an open-label, single-arm, clinical trial. Front Neurol.2018;9:64.
20. Barbanti P et al. Ketogenic diet in migraine: rationale, findings and perspectives. Neurol Sci. 2017;38(Suppl 1):111-115.
21. Murray AJ et al. Novel ketone diet enhances physical and cognitive performance. FASEB J. 2016; 30(12):4012-32.

Milene Brownlow, PhD

Dr. Milene Brownlow is a Nutrition Scientist for the Cognitive Platform at Metagenics. She has earned her PhD from the University of South Florida, studying the role of diet-induced ketosis and calorie restriction on Alzheimer’s pathology. During her postdoctoral fellowship at the Air Force Research Laboratory she investigated nutritional approaches to optimizing brain health and cognitive performance. Dr. Brownlow has extensive experience in designing, managing and executing studies in behavioral neuroscience and has authored over 12 peer-reviewed publications. In her spare time, she enjoys spending time with her husband and their daughter, exploring the beautiful Pacific Northwest.