Brain fuel metabolism, aging, and Alzheimer’s disease

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.

https://www.mdpi.com/1422-0067/21/22/8767/pdf

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

A workflow is presented that integrates gene expression data, proteomic data, and literature-based manual curation to construct multicellular, tissue-specific models of human brain energy metabolism that recapitulate metabolic interactions between astrocytes and various neuron types. Three analyses are applied for gene identification, analysis of omics data, and analysis of physiological states. First, we identify glutamate decarboxylase as a target that may contribute to cell-type and regional specificity in Alzheimer’s disease. Second, the decreased metabolic rate seen in affected brain regions in Alzheimer’s disease is consistent with a suppression of central metabolic gene expression in histopathologically normal neurons. Third, we identify pathways in cholinergic neurons that couple mitochondrial metabolism and cytosolic acetylcholine production, and subsequently find that cholinergic neurotransmission accounts for ∼3% of brain neurotransmission. Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in human tissues, and provide detailed mechanistic insight into high-throughput data analysis.

/pdf/large-scale-in-silico-modeling-of-metabolic-interactions-4epdvb4s49.pdf

Large-scale in silico modeling of metabolic interactions between cell types in the human brain

Postmortem and computed tomographic studies demonstrate many anatomical, morphological, and neurochemical differences between brains of old and young human beings. The variability of the results is great, however, and brains of some old subjects have characteristics of brains of younger controls. Furthermore, important aspects of brain functional activity are not reduced in the elderly. These include resting cerebral oxidative metabolism and "crystallized" intelligence as represented by verbal subtests on the Wechsler Adult Intelligence Scale. In the absence of superimposed disease (which frequently limits aging studies), overall function can be maintained at high and effective levels because of the plasticity and redundancy capabilities of the human brain.

The aging human brain.

Global cerebral blood flow, oxidative brain metabolism, and the cerebral arteriovenous differences of amino acids and ammonia were studied in 20 clinically diagnosed patients with early-onset dementia of Alzheimer type (DAT). Eleven healthy age-matched subjects and 15 healthy young volunteers served as controls. The most prominent abnormality in patients with early-onset DAT was a 44% reduction in the cerebral metabolic rate of glucose and a fourfold increase of lactate production, whereas cerebral blood flow and the cerebral metabolic rate of oxygen were found not to be altered. The cerebral amino-N balance substantially changed in patients with early-onset DAT, showing a massive loss of amino acids and ammonia from the brain, which was indicative of excess protein catabolism due to cell degeneration in the acutely diseased brain. The abnormality found in glucose metabolism may suggest a perturbed control of glycolytic breakdown of glucose and its first oxidation step at the pyruvate dehydrogenase complex level, this thus being of pivotal significance in early-onset DAT.

Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type?

The cerebral blood flow (CBF) and cerebral metabolic rate (CMR) of oxygen, glucose, lactate, pyruvate, ketone bodies, and 24 amino acids were examined in 10 healthy subjects, five 21-24 and five 55-65 years old. The subjects were free from drugs. The results of psychometric and neurological examinations were negative. CBF was determined with the nitrous oxide method on the subjects who were awake and normocapnic and had fasted overnight. No differences were found between the young and the old groups except in arterial levels of four amino acids, viz. aspartic acid, methionine, lysine, and tryptophan. In the whole group of 10 subjects, a significant cerebral net uptake (expressed as median values in mumol X kg-1 X min-1) was found not only for oxygen (1719) and glucose (248), but also for acetoacetate (4.3), D-beta-hydroxybutyrate (6.2), arginine (2.0), leucine (5.2), and isoleucine (1.2). There was a significant net release of lactate (-28). CBF was positively correlated to the CMR of oxygen and D-beta-hydroxybutyrate. Arterial concentrations and CMR were positively correlated for ketone bodies, glutamic acid, proline and taurine. It is of particular interest that the whole group of healthy subjects showed a significant cerebral uptake of branched-chain and dibasic amino acids.

Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids.

Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids: II. PRESENILE DEMENTIA AND NORMAL-PRESSURE HYDROCEPHALUS

Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids in patients with normal pressure hydrocephalus before and after shunting and in normal subjects.

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Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids.

Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids: II. PRESENILE DEMENTIA AND NORMAL-PRESSURE HYDROCEPHALUS

Cerebral blood flow and metabolic rate of oxygen, glucose, lactate, pyruvate, ketone bodies and amino acids in patients with normal pressure hydrocephalus before and after shunting and in normal subjects.