Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

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.

Keywords: SGLT-2 inhibitors; astrocytes; cerebral metabolism; cognition; ketogenic diet; ketone bodies; ketone supplements; neurodegeneration.

Figure 1

Pathways involved in synthesis and catabolism of ketone bodies. AcAc, acetoacetate; Acetyl-CoA, acetyl coenzyme A; BHB, beta-hydroxybutyrate; BHD, beta-hydroxybutyrate dehydrogenase; FFA, free fatty acids; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HMGCS2, 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2; MCFA, medium-chain fatty acids; MCT, monocarboxylate transporter; SCOT, succinyl-CoA:3-ketoacid Coenzyme A transferase; TCA, tricarboxylic acid cycle.

Figure 2

Vicious circle of energy crisis in neurodegenerative disease. The proposed effects of beta-hydroxybutyrate (BHB) on disease mechanisms are illustrated in green, demonstrating an inhibition of oxidative stress, neuroinflammation and mitochondrial dysfunction together with a facilitated ketone oxidation, which results in at least a partially restored metabolism.

Figure 3

Overview of cognitive domains affected by ketogenic interventions in patients with mild cognitive impairment or AD. Overall improvements are demonstrated by green arrows. Illustration is solely based on studies using a randomized-controlled study design (cross-over or parallel groups). Interventions included ketogenic diets [97,98] or supplementation with MCFAs [88,90,91,92,93,94,96] ranging from acute (90 min after ingestion) to 6 months in duration and studies include between 12 and 413 participants.