Abstract
Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.
Highlights
The human brain requires a significant amount of energy for normal brain function and accounts for about 20% of the body’s total energy expenditure at rest, despite the fact that the brain only represents ~2% of the total body weight [1]
This is emphasized in pathological conditions where brain metabolism is disturbed, e.g., in glucose transporter type 1 (GLUT-1) deficiency resulting in impaired cerebral glucose uptake, where clinical symptoms may manifest as seizures, movement disorders, and cognitive impairments [6]
We focus on different ketogenic approaches and describe the metabolic actions of ketone bodies in the brain and highlight key clinical data that support the neuroprotective effects of ketones in diseases of neurodegeneration
Summary
The human brain requires a significant amount of energy for normal brain function and accounts for about 20% of the body’s total energy expenditure at rest, despite the fact that the brain only represents ~2% of the total body weight [1]. An adequate and continuous supply of energy is necessary to maintain brain cellular function since only a limited amount of glycogen is stored inside the brain [5] This is emphasized in pathological conditions where brain metabolism is disturbed, e.g., in glucose transporter type 1 (GLUT-1) deficiency resulting in impaired cerebral glucose uptake, where clinical symptoms may manifest as seizures, movement disorders, and cognitive impairments [6]. When plasma levels of ketone bodies are raised either by fasting, diet or infusion, they are transported to the brain and metabolized in a concentration-dependent manner [10], offering a strategy to alter or enhance cerebral metabolism in disorders with a disturbed glucose metabolism. We focus on different ketogenic approaches and describe the metabolic actions of ketone bodies in the brain and highlight key clinical data that support the neuroprotective effects of ketones in diseases of neurodegeneration
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