Ketosis and the brain

Photo by Fakurian Design on Unsplash

Let’s see what a ketogenic diet (KD) might do for the brain. I will concentrate on two disorders: Epilepsy (in which a KD is an established therapy) and Alzheimer’s disease (in which a KD might be a therapy and our high-carbohydrate diet a contributing cause). There is also a case to be made for Parkinson’s disease.

Epilepsy

It has been known for centuries that fasting can reduce the frequency of seizures in epilepsy (Hippocrates even mentions it). But, this is not a practical long-term strategy. Around the 1920s, doctors noticed that seizures remained under control when they broke the fast with fats, but that seizures rapidly returned when the fast was broken with carbohydrates. Indeed, seizures can return within an hour of injecting glucose.

The use of diet to mimic fasting in epilepsy was suggested by Dr Russell Wilder in 1921. He was the first to coin the term KD, since blood ketones rise both with fasting and with low-carbohydrate eating. In its earliest form it was a severely restricted glucose diet, usually preceded by a period of fasting: 90% of calories from fat, 8% from protein, and 2% from carbohydrates. A diet such as this needs to be administered under medical supervision. This is a therapeutic KD. It is not the nutritional ketogenic diet that I write about on this platform and that induces mild ketosis in a sustainable way.

The therapeutic KD turned out to be highly effective, and it became widely administered because, at the time, drug options were limited and not very effective (bromine, phenobarbital). Real progress had to await the development of animal models of epilepsy in the 1930s, which could be used to trial anti-epileptic drugs (AEDs). This led to the discovery of phenytoin (Dilantin) which was effective for a variety of seizures. With this, and subsequently developed drugs, medication became the treatment of choice and the therapeutic KD was sidelined, mainly because of the challenges the diet imposed (pills were easier, and more in keeping with the medical model).

However, many epileptics taking AEDs remain treatment-resistant or develop complications. This has led to a recent resurgence of interest in the KD as a treatment option. Remarkably, a KD can be effective in drug-resistant epilepsy, attesting to its powerful effect (about a third of drug-resistant epileptics can expect a 90% reduction in seizures). Furthermore, seizures can sometimes remain under control even after the diet is terminated, which means the diet may have modified the disease itself not just the symptoms (something that no AED can do).

How a KD reduces seizures is not fully understood. The KD may reduce neuronal excitability or alter the levels of excitatory and inhibitory neurotransmitters, or be multifactorial involving epigenetic factors for example. There is interest in better understanding the mechanisms, as this could lead to the development of new and novel AEDs. Meanwhile, its success in epilepsy is definitive evidence that a KD can alter brain function, in this case profoundly.

Alzheimer’s disease

The cause and mechanisms of Alzheimer’s disease (AD) are not yet known. One thought-provoking possibility, from a public health perspective, is that AD might be a metabolic disorder. That is, a disorder of energy (glucose) metabolism, perhaps brought on by high carbohydrate consumption.

As a metabolic disorder, there is evidence to suggest that AD combines aspects of type 1 diabetes (insulin deficiency) and type 2 diabetes (insulin resistance). Some researchers are sufficiently convinced to propose that AD be renamed type 3 diabetes, however this is not a majority view. Even if insulin/glucose dysfunction is not the primary cause of AD, there is strong evidence that glucose utilisation in the brain begins to decline early in AD (decades before clinical signs), and it is likely to contribute to the progression of symptoms. Brain imaging studies have shown reduced glucose utilisation prior to clinical signs in critical brain regions, whereas ketone metabolism in those same regions can be normal, assuming ketones are available.

It was not until 1978 that insulin was even known to be in the brain. It is now recognised that brain insulin performs many critical functions — some of which are: cell growth and survival; neurotransmitter synthesis (neuronal signalling molecules); synaptogenesis (new connections between neurones, important for memory and learning), and; brain cholesterol synthesis (cholesterol is crucial for healthy brain function).

Under normal conditions, the brain is dependent on glucose for energy, however unlike other body cells, neurons are not strongly dependent on insulin for the uptake of glucose. However, other cell types in the brain, such as glial cells, are. This makes the brain vulnerable if glucose metabolism becomes dysfunctional or if brain insulin resistance develops. Whether this could arise from high dietary glucose is not known, however, diabetes (and obesity) are risk-factors for AD.

Reducing the brain’s dependence on glucose may circumvent some of these problems. However, fatty-acids and amino acids are not realistic alternative fuels because their entry into the brain is regulated by the blood-brain barrier (BBB) — mostly essential fatty acids and amino acids (that the brain cannot synthesise itself) cross and they’re not used as fuel (they have other important roles). Ketones, however, will easily cross the BBB, and in a dose-dependent way — the more ketones there are in the blood, the more that will cross into the brain. The brain can readily use ketones for energy — ketones bypass insulin resistance and glucose dysfunction. Furthermore, ketones are messenger molecules that up-regulate systems to reduce oxidative stress and inflammation. They are neuro-protective. A keto-adapted metabolism arising from a KD might help rescue stressed brain cells, or be protective for healthy ones.

The developing brain and ketones

The brain won’t be too surprised to find itself being fed ketones, because that’s what it started out with. The developing brain of a foetus and the brain of a new-born breast-feeding infant are keto-adapted. The switch to glucose occurs with weaning, as high-fat mothers’ milk is steadily withdrawn and replaced with low-fat high-carbohydrate food, by convention. At that point the infant brain becomes glucose-dependent and, under normal circumstances, presumably stays that way for life.

A case study

Research into KDs in AD is in its infancy — most of what we know about ketones and AD comes from laboratory studies. In an interesting case study (one patient), ketones were administered orally to a person with advanced AD to raise ketone levels above what a KD could reach. There were improvements of memory, cognition and function, none of which could be achieved by conventional medication. It remains to be seen whether this can be replicated. Increasingly, studies are showing a benefit of ketosis in mild cognitive impairment that might precede AD.

Parkinson’s disease

There is interest in a KD for other neurodegenerative disorders such as Parkinson’s disease (PD) and motor neurone disease, and in neurotrauma (stroke, concussion). I have published a short editorial (in Expert Review of Neurotherapeutics) on the therapeutic potential of ketones in PD (jump to it here). It’s intended for a scientific audience, rather than my writing on this platform, but the message is in the title.

Neuroprotection for the healthy

Meanwhile, a KD may be neuroprotective for people without a neurological disorder, and has benefits that go beyond the brain and address other serious health issues (such as diabetes and obesity). An intriguing observation is that those who have success with a KD frequently take on a more cheerful mood and report a new ‘clarity of thought’, both of which are functions of the brain.

Further reading:

Gassier et al., (2006) Neuroprotective and disease modifying effects of the ketogenic diet.

Ruskin et al., (2012) The nervous system and metabolic dysregulation: Emerging evidence converges on ketogenic diet therapy.

Beds et al., (2015) Aberrant insulin signalling in Alzheimer’s disease: current knowledge.

Acevedo de Lima et al., (2014) Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy

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