Impact of Ketogenic Diet on Neurological Disorders

Authors:

Tasneem Kousar MBBS,

Abeer Sarwar MBBS,

Junaid Kalia MD

Introduction

• Ketogenic diet is a diet rich in fats, moderate proteins and low on carbohydrates.

• The diet was initially developed to treat epilepsy in children

• Over the years, a number of researches are in place to establish its role in neurological function and pathologies

Goal of Ketogenic Diet

• To mimic the biochemical model of fasting

• To utilize the neuroprotective effect of ketones in various brain pathologies

• To decrease overall on inflammatory response to the body and brain.

Types of Ketogenic Diet

• Classic Ketogenic diet

• Targeted Ketogenic diet

• Modified Atkin's diet

• Medium chain triglyceride oil (MCT)

Effects on Brain health

• Ketone bodies are able to cross the blood-brain barrier

• In normal circumstances, glucose is utilized by the body for ATP production. During periods of fasting or starving, ketone bodies become the source of energy

• After crossing the blood brain barrier they can be a source of energy and provide ATP replacing the function of glucose

Figure 1: Three types of ketone bodies

Epilepsy

• Ketogenic diet are well established as a treatment option in pharmacologically resistant epilepsy especially in children

• A ketone diet is started after unresponsiveness to at least 2 epileptic drugs

• The exact anti-epileptic properties of ketone bodies are still unknown

• Many in vivo and in vitro studies are currently studying different molecular targets of ketones bodies. Some of the targets being studied include
• GABA
• Glutamate receptors and transporters
• Histone Deacetylation
• ATP Potassium channels

• The role of ketone bodies is diverse, as it exerts anti-inflammatory, anti-oxidant and mitochondrial effects. It also affects the gut microbe. All of the above can contribute to its anti-epileptic effects.

Neurodegenerative disease

• Glucose Metabolism in brain
• Studies have also shown reduced glucose uptake in Alzheimer's disease.
• The BENEFIC (Brain ENErgy, Fitness, Imaging and Cognition) Trial was conducted to assess the ketones and glucose metabolism via PET (Positron Emission Tomography). The study concluded that ketogenic drink for 6 months showed increased ketone uptake in white matter bypassing glucose deficit and improvement in cognitive function.

• Mitochondrial involvement in brain disease
• The neurodegenerative diseases like Alzheimer's are linked to B-Amyloid protein accumulation in brain that can ultimately causes mitochondrial dysfunction resulting in decreased ATP and eventually cell death.
• Ketogenic diet causes an upregulation of mitochondrial genes as well as genes utilized in metabolism while stimulating the increase in mitochondrial mass.
• This ensures the supply of ATP. The availability of ATP and enhanced mitochondrial function contribute to improved axonal survival and prevents demyelination.
• β-hydroxybutyrate Improves mitochondrial function by decreasing the production of Reactive Oxygen Species (ROS)

• The role of ketones in myelin preservation is still under investigation

Traumatic Brain Injury

• Traumatic brain injury's can results in disruption of the neuronal flow and glucose metabolism. The cerebral cells increase their glucose uptake to maintain the neuronal flow also known as hyperglycolysis.

• Hyperglycemia in the acute recovery phase of brain injury plays detrimental effect.

• It has been proposed that further investigation into the ketogenic diet is needed to understand its potential benefits for traumatic brain injuries and its role with neuro Protection.

Ischemic stroke

• Ketone diet exerts neuroprotective effect by selectively protecting neurons and prolonging their survival from mechanisms that precipitate excitotoxicity and death,

• Ketones also protects from free radical injury in ischemic stroke.

Neuroinflammation

• Migraine is an inflammatory disorder.

• It is characterized by a sterile meningeal neurogenic inflammation which stimulates trigeminal afferent nociceptive neurons and activates mast cells and macrophages which in turn release cytokines, serotonin, histamine and proteases

• KD decreases TNFa (tumor necrosis factor alpha) levels and NFjB (nuclear factor j B) nuclear translocation, inhibits COX2 (cyclooxygenase 2) and microsomal prostaglandin E(2) synthase-1 expression

Neurological Tumors

• Tumor cells have a high demand for glucose and posses limited ability to oxidize ketone bodies.

• Ketones produced with intake of ketogenic diet are able to bypass glucose metabolism and provide ATP to brain cells. The depletion of glucose can starve the tumor cells causing cell death.

• Studies done on patients with brain tumours shows that ketogenic diet have certain benefits that include improved response of the tumor to standard treatment (chemotherapy/radiation) and improvement in quality of life measures (alertness)

Adverse effects of ketogenic diet

• Common side effects include, Flu-like symptoms, headaches and muscle aches. This is also known as keto flu. The treatment of keto flu is hydration and over the counter electrolytes

• Other side effects are kidney stones, vitamin and mineral deficiencies, and gastrointestinal distress.

• Increased intake of saturated fat can lead to dyslipidemia and coronary artery diseases.

Further Reading

• McDonald, T. J. W., & Cervenka, M. C. (2018). Ketogenic Diets for Adult Neurological Disorders. Neurotherapeutics, 15(4), 1018–1031. https://doi.org/10.1007/s13311-018-0666-8

• Kim DY;Simeone KA;Simeone TA;Pandya JD;Wilke JC;Ahn Y;Geddes JW;Sullivan PG;Rho JM; (n.d.). Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Annals of neurology. Retrieved October 24, 2021, from https://pubmed.ncbi.nlm.nih.gov/25899847

• J;, J. N. J. W. H. Z. N. M. R. (n.d.). Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. International journal of molecular sciences. Retrieved October 24, 2021, from https://pubmed.ncbi.nlm.nih.gov/33233502

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