The effects of the ß1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

AIM: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a ß3-adrenergic receptor (ß3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a ß1-AR antagonist could suppress these unwanted effects and increase the stimulation of the ß3-AR and ß2-AR in BAT. METHODS: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the ß1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. RESULTS: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. CONCLUSION: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.

OBJECTIVE: A ketogenic diet (KD) characterized by very low carbohydrate intake and high fat consumption may simultaneously induce weight loss and be cardioprotective. The "thrifty substrate hypothesis" posits that ketone bodies are more energy efficient compared with other cardiac oxidative substrates such as fatty acids. This work aimed to study whether a KD with presumed increased myocardial ketone body utilization reduces cardiac fatty acid uptake and oxidation, resulting in decreased myocardial oxygen consumption (MVO2 ). METHODS: This randomized controlled crossover trial examined 11 individuals with overweight or obesity on two occasions: (1) after a KD and (2) after a standard diet. Myocardial free fatty acid (FFA) oxidation, uptake, and esterification rate were measured using dynamic [11 C]palmitate positron emission tomography (PET)/computed tomography, whereas MVO2 and myocardial external efficiency (MEE) were measured using dynamic [11 C]acetate PET. RESULTS: The KD increased plasma ß-hydroxybutyrate, reduced myocardial FFA oxidation (p < 0.01) and uptake (p = 0.03), and increased FFA esterification (p = 0.03). No changes were observed in MVO2 (p = 0.2) or MEE (p = 0.87). CONCLUSIONS: A KD significantly reduced myocardial FFA uptake and oxidation, presumably by increasing ketone body oxidation. However, this change in cardiac substrate utilization did not improve MVO2 , speaking against the thrifty substrate hypothesis.

Synthesis and Preclinical Evaluation of 22-[18F]Fluorodocosahexaenoic Acid as a Positron Emission Tomography Probe for Monitoring Brain Docosahexaenoic Acid Uptake Kinetics.

Docosahexaenoic acid [22:6(n-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated brain DHA uptake and metabolism are found in individuals carrying the APOE4 allele, which increases the genetic risk for Alzheimer's disease (AD), and are implicated in the progression of several neurodegenerative disorders. However, there are limited tools to assess brain DHA kinetics in vivo that can be translated to humans. Here, we report the synthesis of an ω-radiofluorinated PET probe of DHA, 22-[18F]fluorodocosahexaenoic acid (22-[18F]FDHA), for imaging the uptake of DHA into the brain. Using the nonradiolabeled 22-FDHA, we confirmed that fluorination of DHA at the ω-position does not significantly alter the anti-inflammatory effect of DHA in microglial cells. Through dynamic PET-MR studies using mice, we observed the accumulation of 22-[18F]FDHA in the brain over time and estimated DHA's incorporation coefficient (K*) using an image-derived input function. Finally, DHA brain K* was validated using intravenous administration of 15 mg/kg arecoline, a natural product known to increase the DHA K* in rodents. 22-[18F]FDHA is a promising PET probe that can reveal altered lipid metabolism in APOE4 carriers, AD, and other neurologic disorders. This new probe, once translated into humans, would enable noninvasive and longitudinal studies of brain DHA dynamics by guiding both pharmacological and nonpharmacological interventions for neurodegenerative diseases.

Cardiorenal ketone metabolism: a positron emission tomography study in healthy humans.

Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, 11C-acetoacetate (11C-AcAc), in the heart and kidney compared to 11C-acetate (11C-Ac), which is a well-validated metabolic radiotracer. Both tracers were highly metabolized by the left ventricle and the renal cortex. In the heart, kinetic rates were similar for both tracers. But in the renal cortex, uptake of 11C-Ac was higher compared to 11C-AcAc, while the reverse was observed for the clearance. Interestingly, infusion of 11C-AcAc led to a significantly delayed release of radioactivity in the renal medulla and pelvis, a phenomenon not observed with 11C-Ac. This suggests an equilibrium of 11C-AcAc with the other ketone, 11C-D-beta-hydroxybutyrate, and a different clearance profile. Overall, this suggests that in the kidney, the absorption and metabolism of 11C-AcAc is different compared to 11C-Ac. This dual tracer PET protocol provides the opportunity to explore the relative importance of ketone metabolism in cardiac and renal diseases, and to improve our mechanistic understanding of new metabolic interventions targeting these two organs.

Non-calcified active atherosclerosis plaque detection with 18F-NaF and 18F-FDG PET/CT dynamic imaging.

Arterial inflammation is an indicator of atheromatous plaque vulnerability to detach and to obstruct blood vessels in the heart or in the brain thus causing heart attack or stroke. To date, it is difficult to predict the plaque vulnerability. This study was aimed to assess the behavior of 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake in the aorta and iliac arteries as a function of plaque density on CT images. We report metabolically active artery plaques associated to inflammation in the absence of calcification. 18 elderly volunteers were recruited and imaged with computed tomography (CT) and positron emission tomography (PET) with 18F-NaF and 18F-FDG. A total of 1338 arterial segments were analyzed, 766 were non-calcified and 572 had calcifications. For both 18F-NaF and 18F-FDG, the mean SUV values were found statistically significantly different between non-calcified and calcified artery segments. Clustering CT non-calcified segments, excluding blood, resulted in two clusters C1 and C2 with a mean density of 30.63 ± 5.06 HU in C1 and 43.06 ± 4.71 HU in C2 (P < 0.05), and their respective SUV were found statistically different in 18F-NaF and 18F-FDG. The 18F-NaF images showed plaques not detected on CT images, where the 18F-FDG SUV values were high in comparison to artery walls without plaques. The density on CT images alone corresponding to these plaques could be further investigated to see whether it can be an indicator of the active plaques.

Radiosynthesis of 20-[18F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.

Dysreglulated brain arachidonic acid (AA) metabolism is involved in chronic inflammation and is influenced by apolipoprotein E4 (APOE4) genotype, the strongest genetic risk factor of late-onset Alzheimer's disease (AD). Visualization of AA uptake and distribution in the brain can offer insight into neuroinflammation and AD pathogenesis. Here we present a novel synthesis and radiosynthesis of 20-[18F]fluoroarachidonic acid ([18F]-FAA) for PET imaging using a convergent route and a one-pot, single-purification radiolabeling procedure, and demonstrate its brain uptake in human ApoE4 targeted replacement (ApoE4-TR) mice. By examining p38 phosphorylation in astrocytes, we found that fluorination of AA at the ω-position did not significantly alter its biochemical role in cells. The brain incorporation coefficient (K*) of [18F]-FAA was estimated via multiple methods by using an image-derived input function from the right ventricle of the heart as a proxy of the arterial input function and brain tracer concentrations assessed by dynamic PET-MR imaging. This new synthetic approach should facilitate the practical [18F]-FAA production and allow its translation into clinical use, making investigations of dysregulation of lipid metabolism more feasible in the study of neurodegenerative diseases.

Exercise Capacity and Perceived Exertion on Treadmill Stress Test Performed While Wearing vs Without a Surgical Mask: A Randomized Clinical Trial in Healthy Adults.

Background: The graded exercise treadmill stress test (GXT) is among the most frequently performed tests in cardiology. The COVID-19 pandemic led many healthcare facilities to require patients to wear a mask during the test. This study evaluated the effect of wearing a surgical face mask on exercise capacity and perceived exertion. Methods: In this prospective, randomized crossover trial, 35 healthy adults performed a GXT using the Bruce protocol while wearing a surgical mask, and without a mask. The primary outcome was exercise capacity in metabolic equivalents (MET), and the secondary outcome was exercise perception on the modified Borg scale (from 0 to 10). Effort duration, heart rate, oxygen saturation, and blood pressure were also analyzed. Results: Exercise capacity was reduced by 0.4 MET (95% confidence interval [CI] -0.7 to -0.2) during the GXT with a mask (11.8 ± 2.7 vs 12.3 ± 2.5 MET, P = 0.001), and the final perceived effort increased by 0.5 points (95% CI 0.2 to 0.8; 8.4 ± 1.3 vs 7.9 ± 1.6, P = 0.004). Effort duration was cut down by 24 seconds (CI -0:39 to -0:09; 10:03 ± 2:30 vs 10:27 ± 2:16 [minutes:seconds], P = 0.003). Oxygen saturation was slightly lower at the end of the test when participants wore a mask. No significant differences occurred in heart rate or blood pressure during the test. Conclusion: Wearing a surgical mask causes a statistically significant decrease in exercise capacity and increase in perceived exertion. This small effect is not clinically significant for the interpretation of test results.

Introduction: L'épreuve d'effort gradué sur tapis roulant (GXT, de l'anglais graded exercise test) compte parmi les épreuves les plus fréquemment réalisées en cardiologie. La pandémie de COVID-19 a poussé de nombreux établissements de soins de santé à exiger aux patients le port du masque durant l'épreuve. La présente étude portait sur l'évaluation des effets du port du masque chirurgical sur la capacité à l'effort et l'effort perçu. Méthodes: Dans cet essai croisé prospectif, 35 adultes en bonne santé ont réalisé une GXT selon le protocole de Bruce, avec le port du masque chirurgical et sans le port du masque. Le principal critère d'évaluation était la capacité à l'effort exprimée en équivalents métaboliques (MET, de l'anglais Metabolic Equivalent of Task), et le critère secondaire était la perception de l'effort selon l'échelle de Borg modifiée (de 0 à 10). La durée de l'effort, la fréquence cardiaque, la saturation en oxygène et la pression artérielle ont également fait l'objet de l'analyse. Résultats: La capacité à l'effort était réduite de 0,4 MET (intervalle de confiance [IC] à 95 % de ­0,7 à ­0,2) durant la GXT réalisée avec le port du masque (11,8 ± 2,7 vs 12,3 ± 2,5 MET, P = 0,001), et l'effort perçu final avait augmenté de 0,5 point (IC à 95 % de 0,2 à 0,8 ; 8,4 ± 1,3 vs 7,9 ± 1,6, P = 0,004). La durée de l'effort était réduite de 24 secondes (IC à 95 % de ­0:39 à ­0:09 ; 10:03 ± 2:30 vs 10:27 ± 2:16 [minutes:secondes], P = 0,003). La saturation en oxygène était légèrement plus faible à la fin de l'épreuve lorsque les participants portaient le masque. Aucune différence significative de la fréquence cardiaque et de la pression artérielle n'est apparue durant l'épreuve. Conclusion: Le port du masque chirurgical entraîne une diminution statistiquement significative de la capacité à l'effort et une augmentation de l'effort perçu. Cet effet minime n'est pas cliniquement significatif pour l'interprétation des résultats de l'épreuve.

A ketogenic intervention improves dorsal attention network functional and structural connectivity in mild cognitive impairment.

Ketones, the brain's alternative fuel to glucose, bypass the brain glucose deficit and improve cognition in mild cognitive impairment (MCI). Our goal was to assess the impact of a 6-month ketogenic intervention on the functional connectivity within eight major brain resting-state networks, and its possible relationship to improved cognitive outcomes in the BENEFIC trial. MCI participants were randomized to a placebo (n = 15) or ketogenic medium chain triglyceride (kMCT; n = 17) intervention. kMCT was associated with increased functional connectivity within the dorsal attention network (DAN), which correlated to improvement in cognitive tests targeting attention. Ketone uptake (11C-acetoacetate PET) specifically in DAN cortical regions was highly increased in the kMCT group and was directly associated with the improved DAN functional connectivity. Analysis of the structural connectome revealed increased fiber density within the DAN following kMCT. Our findings suggest that ketones in MCI may prove beneficial for cognition at least in part because they improve brain network energy status, functional connectivity and axonal integrity.

A ketogenic supplement improves white matter energy supply and processing speed in mild cognitive impairment.

INTRODUCTION: White matter (WM) energy supply is crucial for axonal function and myelin maintenance. An exogenous source of ketones, the brain's alternative fuel to glucose, bypasses the brain's glucose-specific energy deficit and improves cognitive outcomes in mild cognitive impairment (MCI). How an additional supply of ketones affects glucose or ketone uptake in specific WM fascicles in MCI has not previously been reported. METHODS: This 6-month interventional study included MCI participants randomized to a placebo (n = 16) or ketogenic medium chain triglyceride (kMCT; n = 17) drink. A neurocognitive battery and brain imaging were performed pre- and post-intervention. WM fascicle uptake of ketone and glucose and structural properties were assessed using positron emission tomography and diffusion imaging, respectively. RESULTS: Ketone uptake was increased in the kMCT group by 2.5- to 3.2-fold in all nine WM fascicles of interest (P < .001), an effect seen both in deep WM and in fascicle cortical endpoints. Improvement in processing speed was positively associated with WM ketone uptake globally and in individual fascicles, most importantly the fornix (r = +0.61; P = .014). DISCUSSION: A 6-month kMCT supplement improved WM energy supply in MCI by increasing ketone uptake in WM fascicles. The significant positive association with processing speed suggests that ketones may have a role in myelin integrity in MCI.

Quantitative SPECT (QSPECT) at high count rates with contemporary SPECT/CT systems.

BACKGROUND: Accurate QSPECT is crucial in dosimetry-based, personalized radiopharmaceutical therapy with 177Lu and other radionuclides. We compared the quantitative performance of three NaI(Tl)-crystal SPECT/CT systems equipped with low-energy high-resolution collimators from two vendors (Siemens Symbia T6; GE Discovery 670 and NM/CT 870 DR). METHODS: Using up to 14 GBq of 99mTc in planar mode, we determined the calibration factor and dead-time constant under the assumption that these systems have a paralyzable behaviour. We monitored their response when one or both detectors were activated. QSPECT capability was validated by SPECT/CT imaging of a customized NEMA phantom containing up to 17 GBq of 99mTc. Acquisitions were reconstructed with a third-party ordered subset expectation maximization algorithm. RESULTS: The Siemens system had a higher calibration factor (100.0 cps/MBq) and a lower dead-time constant (0.49 µs) than those from GE (75.4-87.5 cps/MBq; 1.74 µs). Activities of up to 3.3 vs. 2.3-2.7 GBq, respectively, were quantifiable by QSPECT before the observed count rate plateaued or decreased. When used in single-detector mode, the QSPECT capability of the former system increased to 5.1 GBq, whereas that of the latter two systems remained independent of the detectors activation mode. CONCLUSION: Despite similar hardware, SPECT/CT systems' response can significantly differ at high count rate, which impacts their QSPECT capability in a post-therapeutic setting.

The regional effect of serum hormone levels on cerebral blood flow in healthy nonpregnant women.

Sex hormones estrogen (EST) and progesterone (PROG) have received increased attention for their important physiological action outside of reproduction. While studies have shown that EST and PROG have significant impacts on brain function, their impact on the cerebrovascular system in humans remains largely unknown. To address this, we used a multi-modal magnetic resonance imaging (MRI) approach to investigate the link between serum hormones in the follicular phase and luteal phase of the menstrual cycle (MC) with measures of cerebrovascular function (cerebral blood flow [CBF]) and structure (intracranial artery diameter). Fourteen naturally cycling women were recruited and assessed at two-time points of their MC. CBF was derived from pseudo-continuous arterial spin labeling while diameters of the internal carotid and basilar artery was assessed using time of flight magnetic resonance angiography, blood samples were performed after the MRI. Results show that PROG and EST had opposing and spatially distinct effects on CBF: PROG correlated negatively with CBF in anterior brain regions (r = -.86, p < .01), while EST correlations were positive, yet weak and most prominent in posterior areas (r = .78, p < .01). No significant correlations between either hormone or intracranial artery diameter were observed. These results show that EST and PROG have opposing and regionally distinct effects on CBF and that this relationship is likely not due to interactions with large intracranial arteries. Considering that CBF in healthy women appears tightly linked to their current hormonal state, future studies should consider assessing MC-related hormone fluctuations in the design of functional MRI studies in this population.

The feasibility, reliability, and incremental value of two-dimensional speckle-tracking for the detection of significant coronary stenosis after treadmill stress echocardiography.

BACKGROUND: Two-dimensional speckle-tracking echocardiography (STE) may help detect coronary artery disease (CAD) when combined with dobutamine stress echocardiography. However, few studies have explored STE with exercise stress echocardiography (ESE). We aimed to evaluate the feasibility, reliability, and incremental value of STE combined with treadmill ESE compared to treadmill ESE alone to detect CAD. METHODS: We conducted a case-control study of all consecutive patients with abnormal ESE in 2018-2020 who subsequently underwent coronary angiography within a six-month interval. We 1:1 propensity score-matched these patients to those with a normal ESE. Two blinded operators generated a 17-segment bull's-eye map of longitudinal strain (LS). We utilized the mean differences between stress and baseline LS values in segments 13-17, segment 17, and segments 15-16 to create receiver operator curves for the overall examination, the left anterior descending artery (LAD), and the non-LAD territories, respectively. RESULTS: We excluded 61 STEs from 201 (30.3%) eligible ESEs; 47 (23.4%) because of suboptimal image quality and 14 (7.0%) because of excessive heart rate variability precluding the calculation of a bull's-eye map. After matching, a total of 102 patients were included (51 patients in each group). In the group with abnormal ESE patients (mean age 66.4 years, 39.2% female), 64.7% had significant CAD (> 70% stenosis) at coronary angiogram. In the group with normal ESE patients (mean age 65.1 years, 35.3% female), 3.9% were diagnosed with a new significant coronary stenosis within one year. The intra-class correlation for global LS was 0.87 at rest and 0.92 at stress, and 0.84 at rest, and 0.89 at stress for the apical segments. The diagnostic accuracy of combining ESE and STE was superior to visual assessment alone for the overall examination (area under the curve (AUC) = 0.89 vs. 0.84, p = 0.025), the non-LAD territory (AUC = 0.83 vs. 0.70, p = 0.006), but not the LAD territory (AUC = 0.79 vs. 0.73, p = 0.11). CONCLUSIONS: Two-dimensional speckle-tracking combined with treadmill ESE is relatively feasible, reliable, and may provide incremental diagnostic value for the detection and localization of significant CAD.

Cross-validation of a non-invasive positron detector to measure the arterial input function for pharmacokinetic modelling in dynamic positron emission tomography.

Kinetic modeling of positron emission tomography (PET) data can assess index rate of uptake, metabolism and predict disease progression more accurately than conventional static PET. However, it requires knowledge of the time-course of the arterial blood radioactivity concentration, called the arterial input function (AIF). The gold standard to acquire the AIF is by invasive means. The purpose of this study was to validate a previously developed dual readout scintillating fiber-based non-invasive positron detector, hereinafter called non-invasive detector (NID), developed to determine the AIF for dynamic PET measured from the human radial artery. The NID consisted of a 3 m long plastic scintillating fiber with each end coupled to a 5 m long transmission fiber followed by a silicon photomultiplier. The scintillating fiber was enclosed inside the grooves of a plastic cylindrical shell. Two sets of experiments were performed to test the NID against a previously validated microfluidic positron detector. A closed-loop microfluidic system combined with a wrist phantom was used. During the first experiment, the three PET radioisotopes 18F, 11C and 68Ga were tested. After optimizing the detector, a second series of tests were performed using only 18F and 11C. The maximum pulse amplitude to electronic noise ratio was 52 obtained with 11C. Linear regressions showed a linear relation between the two detectors. These preliminary results show that the NID can accurately detect positrons from a patient's wrist and has the potential to non-invasively measure the AIF during a dynamic PET scan. The accuracy of these measurements needs to be determined.

Fascicle- and Glucose-Specific Deterioration in White Matter Energy Supply in Alzheimer's Disease.

BACKGROUND: White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer's disease (AD), glucose and ketones, the brain's two main fuels, are rarely quantified in white matter in AD. OBJECTIVE: Using a dual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolism in specific white matter fascicles associated with mild cognitive impairment (MCI; n = 51) and AD (n = 13) compared to cognitively healthy age-matched controls (Controls; n = 14). METHODS: Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18F-fluorodeoxyglucose) and ketone (11C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle. RESULTS: The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (-22%; p = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD. CONCLUSION: To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum.

Selection of the optimal intensity normalization region for FDG-PET studies of normal aging and Alzheimer's disease.

The primary method for measuring brain metabolism in humans is positron emission tomography (PET) imaging using the tracer 18F-fluorodeoxyglucose (FDG). Standardized uptake value ratios (SUVR) are commonly calculated from FDG-PET images to examine intra- and inter-subject effects. Various reference regions are used in the literature of FDG-PET studies of normal aging, making comparison between studies difficult. Our primary objective was to determine the optimal SUVR reference region in the context of healthy aging, using partial volume effect (PVE) and non-PVE corrected data. We calculated quantitative cerebral metabolic rates of glucose (CMRg) from PVE-corrected and non-corrected images from young and older adults. We also investigated regional atrophy using magnetic resonance (MR) images. FreeSurfer 6.0 atlases were used to explore possible reference regions of interest (ROI). Multiple regression was used to predict CMRg data, in each FreeSurfer ROI, with age and sex as predictors. Age had the least effect in predicting CMRg for PVE corrected data in the pons (r2 = 2.83 × 10-3, p = 0.67). For non-PVE corrected data age also had the least effect in predicting CMRg in the pons (r2 = 3.12 × 10-3, p = 0.67). We compared the effects of using the whole brain or the pons as a reference region in PVE corrected data in two regions susceptible to hypometabolism in Alzheimer's disease, the posterior cingulate and precuneus. Using the whole brain as a reference region resulted in non-significant group differences in the posterior cingulate while there were significant differences between all three groups in the precuneus (all p < 0.004). When using the pons as a reference region there was significant differences between all groups for both the posterior cingulate and the precuneus (all p < 0.001). Therefore, the use of the pons as a reference region is more sensitive to hypometabism changes associated with Alzheimer's disease than the whole brain.

Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney.

There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer 11C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a "super fuel" in cardiac and chronic kidney diseases.

A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment.

INTRODUCTION: Unlike for glucose, uptake of the brain's main alternative fuel, ketones, remains normal in mild cognitive impairment (MCI). Ketogenic medium chain triglycerides (kMCTs) could improve cognition in MCI by providing the brain with more fuel. METHODS: Fifty-two subjects with MCI were blindly randomized to 30 g/day of kMCT or matching placebo. Brain ketone and glucose metabolism (quantified by positron emission tomography; primary outcome) and cognitive performance (secondary outcome) were assessed at baseline and 6 months later. RESULTS: Brain ketone metabolism increased by 230% for subjects on the kMCT (P < .001) whereas brain glucose uptake remained unchanged. Measures of episodic memory, language, executive function, and processing speed improved on the kMCT versus baseline. Increased brain ketone uptake was positively related to several cognitive measures. Seventy-five percent of participants completed the intervention. DISCUSSION: A dose of 30 g/day of kMCT taken for 6 months bypasses a significant part of the brain glucose deficit and improves several cognitive outcomes in MCI.

Links Between Metabolic and Structural Changes in the Brain of Cognitively Normal Older Adults: A 4-Year Longitudinal Follow-Up.

We aimed to longitudinally assess the relationship between changing brain energy metabolism (glucose and acetoacetate) and cognition during healthy aging. Participants aged 71 ± 5 year underwent cognitive evaluation and quantitative positron emission tomography (PET) and magnetic resonance imaging (MRI) scans at baseline (N = 25) and two (N = 25) and four (N = 16) years later. During the follow-up, the rate constant for brain extraction of glucose (Kglc) declined by 6%-12% mainly in the temporo-parietal lobes and cingulate gyri (p ≤ 0.05), whereas brain acetoacetate extraction (Kacac) and utilization remained unchanged in all brain regions (p ≥ 0.06). Over the 4 years, cognitive results remained within the normal age range but an age-related decline was observed in processing speed. Kglc in the caudate was directly related to performance on several cognitive tests (r = +0.41 to +0.43, all p ≤ 0.04). Peripheral insulin resistance assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) was significantly inversely related to Kglc in the thalamus (r = -0.44, p = 0.04) and in the caudate (r = -0.43, p = 0.05), and also inversely related to executive function, attention and processing speed (r = -0.45 to -0.53, all p ≤ 0.03). We confirm in a longitudinal setting that the age-related decline in Kglc is directly associated with declining performance on some tests of cognition but does not significantly affect Kacac.

Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. OBJECTIVE: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. METHODS: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. RESULTS: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. CONCLUSION: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.