Betahydroxybutyrate Consumption in Autopsy Brain Tissue from Alzheimer’s Disease Subjects

Background: Alzheimer’s disease (AD) features perturbed brain glucose utilization, which could contribute to brain bioenergetic failure. This led some to consider using ketone bodies to enhance AD brain bioenergetics and treat AD. Objective: We evaluated the rate at which brain homogenates from persons with Alzheimer’s disease (AD) metabolize D-β-hydroxybutyrate (BHB). Methods: We homogenized pieces of temporal cortex from frozen autopsy brains obtained from recently deceased AD subjects (n = 4), and age-matched subjects that did not have clinical AD (n = 3). Measuring the rate of CO2 production that followed the introduction of radiolabeled BHB to the homogenates yielded a BHB utilization rate. Results: Compared to the control homogenates, the BHB-supported CO2 production rate was 66%lower in the AD homogenates (p < 0.05). Conclusions: AD brains can utilize BHB, albeit less robustly than control brains. In conjunction with a previous study that demonstrated reduced glucose utilization in AD brain homogenates, our BHB data provide further evidence of AD brain mitochondrial dysfunction or altered mitochondrial biology.

A Dietary Ketone Ester Normalizes Abnormal Behavior in a Mouse Model of Alzheimer’s Disease

Because of a decreased sensitivity toward insulin, a key regulator of pyruvate dehydrogenase (PDH), Alzheimer’s patients have lower brain glucose utilization with reductions in Tricarboxylic Acid (TCA) cycle metabolites such as citrate, a precursor to n-acetyl-aspartate. In the 3xTgAd mouse model of Alzheimer’s disease (AD), aging mice also demonstrate low brain glucose metabolism. Ketone metabolism can overcome PDH inhibition and restore TCA cycle metabolites, thereby enhancing amino acid biosynthesis. A ketone ester of d-β-hydroxybutyrate was incorporated into a diet (Ket) and fed to 3xTgAd mice. A control group was fed a calorically matched diet (Cho). At 15 months of age, the exploratory and avoidance-related behavior patterns of the mice were evaluated. At 16.5 months of age, the animals were euthanized, and their hippocampi were analyzed for citrate, α-ketoglutarate, and amino acids. In the hippocampi of the Ket-fed mice, there were higher concentrations of citrate and α-ketoglutarate as well as higher concentrations of glutamate, aspartate and n-acetyl-aspartate compared with controls. There were positive associations between (1) concentrations of aspartate and n-acetyl-aspartate (n = 14, R = 0.9327), and (2) α-ketoglutarate and glutamate (n = 14, R = 0.8521) in animals maintained on either diet. Hippocampal n-acetyl-aspartate predicted the outcome of several exploratory and avoidance-related behaviors. Ketosis restored citrate and α-ketoglutarate in the hippocampi of aging mice. Higher concentrations of n-acetyl-aspartate corresponded with greater exploratory activity and reduced avoidance-related behavior.

Dietary Neuroketotherapeutics for Alzheimer’s Disease: An Evidence Update and the Potential Role for Diet Quality

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with growing prevalence as the global population ages. Currently available treatments for AD have minimal efficacy and there are no proven treatments for its prodrome, mild cognitive impairment (MCI). AD etiology is not well understood and various hypotheses of disease pathogenesis are currently under investigation. A consistent hallmark in patients with AD is reduced brain glucose utilization; however, evidence suggests that brain ketone metabolism remains unimpaired, thus, there is a great deal of increased interest in the potential value of ketone-inducing therapies for the treatment of AD (neuroketotherapeutics; NKT). The goal of this review was to discuss dietary NKT approaches and mechanisms by which they exert a possible therapeutic benefit, update the evidence available on NKTs in AD and consider a potential role of diet quality in the clinical use of dietary NKTs. Whether NKTs affect AD symptoms through the restoration of bioenergetics, the direct and indirect modulation of antioxidant and inflammation pathways, or both, preliminary positive evidence suggests that further study of dietary NKTs as a disease-modifying treatment in AD is warranted.

Cellular Origin of [18F]FDG-PET Imaging Signals During Ceftriaxone-Stimulated Glutamate Uptake: Astrocytes and Neurons

Ceftriaxone stimulates astrocytic uptake of the excitatory neurotransmitter glutamate, and it is used to treat glutamatergic excitotoxicity that becomes manifest during many brain diseases. Ceftriaxone-stimulated glutamate transport was reported to drive signals underlying [18F]fluorodeoxyglucose-positron emission tomographic ([18F]FDG-PET) metabolic images of brain glucose utilization and interpreted as supportive of the notion of lactate shuttling from astrocytes to neurons. This study draws attention to critical roles of astrocytes in the energetics and imaging of brain activity, but the results are provocative because (1) the method does not have cellular resolution or provide information about downstream pathways of glucose metabolism, (2) neuronal and astrocytic [18F]FDG uptake were not separately measured, and (3) strong evidence against lactate shuttling was not discussed. Evaluation of potential metabolic responses to ceftriaxone suggests lack of astrocytic specificity and significant contributions by pre- and postsynaptic neuronal compartments. Indeed, astrocytic glycolysis may not make a strong contribution to the [18F]FDG-PET signal because partial or complete oxidation of one glutamate molecule on its uptake generates enough ATP to fuel uptake of 3 to 10 more glutamate molecules, diminishing reliance on glycolysis. The influence of ceftriaxone on energetics of glutamate-glutamine cycling must be determined in astrocytes and neurons to elucidate its roles in excitotoxicity treatment.

Elevated glycemia and brain glucose utilization predict BDNF lowering since early life

Obesity and diabetes associate with neurodegeneration. Brain glucose and BDNF are fundamental in perinatal development. BDNF is related to brain health, food intake and glucose metabolism. We characterized the relationship between glycemia and/or brain glucose utilization (by 18FDG-PET during fasting and glucose loading), obesity and BDNF in 4-weeks old (pre-obese) and 12-weeks old (obese) Zucker fa/fa rats, and their age-matched fa/+ controls. In 75 human infants, we assessed cord blood BDNF and glucose levels, appetite regulating hormones, body weight and maternal factors. Young and adult fa/fa rats showed glucose intolerance and brain hyper-utilization compared to controls. Glycemia and age were positively related to brain glucose utilization, and were negative predictors of BDNF levels. In humans, fetal glycemia was dependent on maternal glycemia at term, and negatively predicted BDNF levels. Leptin levels were associated with higher body weight and lower BDNF levels. Glucose intolerance and elevated brain glucose utilization already occur in young, pre-obese rats, suggesting that they precede obesity onset in Zucker fatty rats. Glycemic elevation and brain glucose overexposure predict circulating BDNF deficiency since perinatal and early life. Future studies should evaluate whether the control of maternal and fetal glycemia during late intrauterine development can prevent these unfavorable interactions.