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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 (

Brain glucose uptake has long been recognized to be reduced in Alzheimer’s disease (AD) but was mainly assumed to be a consequence of reduced neuronal activity. More recently, several studies challenged this concept by showing that brain glucose hypometabolism was also present in individuals at high risk for AD before the presence of any cognitive symptoms. Thus, it is of great interest to know whether cognitive decline can be prevented or delayed if the glucose metabolism defect is at least partly corrected or bypassed. The ketones β-hydroxybutyrate and acetoacetate are the brain’s main alternative fuel to glucose, and their uptake in mild cognitive impairment (MCI) and mild to moderate AD is similar to that seen in healthy age-matched controls. Based on these findings, it is conceivable that ketones could be used to help rescue brain fuel supply during aging. Evidence from published clinical trials showed that increasing ketone availability to the brain via nutritional ketosis can have a beneficial effect on brain energy metabolism and cognitive outcomes in both MCI and mild to moderate AD. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet or ketogenic supplements, such as medium-chain triglycerides containing the eight- and ten-carbon fatty acids, octanoate and decanoate. Given the acute dependence of the brain on its energy supply and the ineffectiveness of current therapeutic strategies aimed at AD, it seems reasonable that consideration be given to correcting the underlying problem of deteriorating brain glucose uptake observed with aging.

Introduction Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI). Methods Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44). Results Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail‐Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre‐intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged. Conclusions This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to 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.

Background Medical societies and funding agencies strongly recommend that patients be included as partners in research publications and grant applications. Although this “top-down” approach is certainly efficient at forcing this new and desirable type of collaboration, our past experience demonstrated that it often results in an ambiguous relationship as not yet well integrated into the cultures of either patients’ or the researchers’. The question our group raised from this observation was: “How to generate a cultural shift toward a fruitful and long-lasting collaboration between patients and researchers? A “bottom-up” approach was key to our stakeholders. The overall objective was to build a trusting and bidirectional-ecosystem between patients and researchers. The specific objectives were to document: 1) the steps that led to the development of the first patient-partner strategic committee within a research center in the Province of Québec; 2) the committee’s achievements after 3 years. Methods Eighteen volunteer members, 12 patient-partners and 6 clinician/institutional representatives, were invited to represent the six research themes of the Centre de recherche du CHU de Sherbrooke (CRCHUS) (Quebec, Canada). Information on the services offered by Committee was disseminated internally and to external partners. Committee members satisfaction was evaluated. Results From May 2017 to April 2020, members attended 29 scheduled and 6 ad hoc meetings and contributed to activities requiring over 1000 h of volunteer time in 2018–2019 and 1907 h in the 2019–2020 period. The Committee’s implication spanned governance, expertise, and knowledge transfer in research. Participation in these activities increased annually at local, provincial, national and international levels. The Patient-Partner Committee collaborated with various local (n = 7), provincial (n = 6) and national (n = 4) partners. Member satisfaction with the Committee’s mandate and format was 100%. Conclusions The CRCHUS co-constructed a Patient-Partner Strategic Committee which resulted in meaningful bilateral, trusting and fruitful collaborations between patients, researchers and partners. The “bottom-up” approach - envisioned and implemented by the Committee, where the expertise and the needs of patients complemented those of researchers, foundations, networks and decision-makers - is key to the success of a cultural shift. The CRCHUS Committee created a hub to develop the relevant intrinsic potential aimed at changing the socio-cultural environment of science.

INTRODUCTIONWhite matter (WM) energy supply is crucial for axonal function and myelin maintenance. Providing ketones, the brain’s alternative fuel to glucose, is a therapeutic strategy to bypass the brain’s glucose-specific energy deficit 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 described.METHODSThis 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.RESULTSKetone uptake was increased by 2.5 to 3.2-fold in nine fascicles of interest (P < 0.001) only in the kMCT group, an effect seen both in deep WM and in fascicle cortical endpoints. Improvement in processing speed was associated with WM ketone uptake globally and in individual fascicles, most importantly the fornix (r = +0.61; P = 0.014).DISCUSSIONA 6-month ketogenic supplementation in MCI improved WM energy supply globally. The significant positive association with processing speed suggests that ketones may have a role in myelin integrity in MCI.

Author(s): Nygaard, Haakon B; Kent, Brianne A; Stager, Sam; Slack, Penelope; DeMarco, Mari L; Castellano, Christian‐Alexandre; Rauscher, Alexander; Cunnane, Stephen; Feldman, Howard H

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 p

Objective: Alzheimer disease (AD) is a chronic neurodegenerative disorder that affects millions of individuals worldwide. Symptoms include memory dysfunction and deficits in attention, planning, language, and overall cognitive function. Olfactory dysfunction is a common symptom of AD and evidence supports that it is an early marker. Furthermore, olfactory bulb and entorhinal cortex atrophy are well described in AD. However, in AD, no studies have assessed the olfactory cortex as a whole and if sex effects are observed. Methods: Magnetic Resonance Imaging was used to scan 39 participants with an average age of 72 years and included men and women. AAL Single-Subject Atlas (implemented in PNEURO tool - PMOD 3.8) was used to determine the volume of the olfactory cortex and the hippocampus. Olfactory cortex volume was lower in both men and women AD cases compared with controls. This decrease was more apparent in the left olfactory cortex and was influenced by age. As expected, hippocampal volume was also significantly reduced in AD. However, this was only observed in the male cohort. A significant correlation was observed between levels of education and hippocampal volume in controls that were not detected in the AD participants. Asymmetry was observed in the olfactory cortex volume when comparing left and right volumes in both the control and AD participants, which was not observed in the hippocampus. Results: These data highlight the importance of the role of olfactory cortical atrophy in the pathogenesis of AD and the interplay between the olfactory deficits and degeneration of olfactory regions in the brain.

There is currently no established therapy to treat or prevent Alzheimer’s disease. The ketogenic diet supplies an alternative cerebral metabolic fuel, with potential neuroprotective effects. Our goal was to compare the effects of a modified Mediterranean-ketogenic diet (MMKD) and an American Heart Association Diet (AHAD) on cerebrospinal fluid Alzheimer’s biomarkers, neuroimaging measures, peripheral metabolism, and cognition in older adults at risk for Alzheimer’s. Twenty participants with subjective memory complaints (n = 11) or mild cognitive impairment (n = 9) completed both diets, with 3 participants discontinuing early. Mean compliance rates were 90% for MMKD and 95% for AHAD. All participants had improved metabolic indices following MMKD. MMKD was associated with increased cerebrospinal fluid Aβ42 and decreased tau. There was increased cerebral perfusion and increased cerebral ketone body uptake (11C-acetoacetate PET, in subsample) following MMKD. Memory performance improved after both diets, which may be due to practice effects. Our results suggest that a ketogenic intervention targeted toward adults at risk for Alzheimer’s may prove beneficial in the prevention of cognitive decline.

Mild cognitive impairment (MCI) is often accompanied by metabolic abnormalities and inflammation that might play a role in the development of cognitive impairment. The use of ketogenic medium-chain triglycerides (kMCT) to improve cognition in this population has shown promising results but remains controversial because of the potentially detrimental effect of elevated intake of saturated fatty acids on cardiovascular (CV) health and perhaps inflammatory processes. The primary aim of this secondary data analysis report is to describe changes in cardiometabolic markers and peripheral inflammation during a 6-month kMCT intervention in MCI.Thirty-nine participants with MCI completed the intervention of 30 g/day of either a kMCT drink or calorie-matched placebo (high-oleic acid) for 6 months. Plasma concentrations of cardiometabolic and inflammatory markers were collected before (fasting state) and after the intervention (2 h following the last drink).A mixed model ANOVA analysis revealed a time by group interaction for ketones (P0.001), plasma 8:0 and 10:0 acids (both P0.001) and IL-8 (P = 0.002) with follow up comparison revealing a significant increase in the kMCT group (+48%, P = 0.005), (+3,800 and +4,900%, both P0.001) and (+147%, P0.001) respectively. A main effect of time was observed for insulin (P = 0.004), triglycerides (P = 0.011) and non-esterified fatty acids (P = 0.036).Under these study conditions, 30 g/d of kMCT taken for six months and up to 2-hour before post-intervention testing had minimal effect on an extensive profile of circulating cardiometabolic and inflammatory markers as compared to a placebo calorie-matched drink. Our results support the safety kMCT supplementation in individuals with MCI. The clinical significance of the observed increase in circulating IL-8 levels is presently unknown and awaits future studies.

Butyrate, carnitine and leucine are dietary ingredients that may be ketogenic but whether they are equally or more ketogenic in humans than medium-chain triacylglycerols is unclear. Our objective was to compare the ketogenic effect in healthy adult humans of l -leucine, butyrate, octanoyl-monoacylglycerol (O-MAG) and l -carnitine during a 4 h metabolic study period. Each test substance was taken with a standard breakfast: butyrate (2 or 4 g), O-MAG (5 or 10 g), l -leucine (5 g), or l -carnitine (2 g), and compared to a no treatment Control (n = 13). At the doses provided, butyrate (2 g; 4 g), O-MAG (5 g; 10 g) increased total plasma ketones AUC of 3.5, 5.0, 1.5, and 2.7-fold (P ≤ 0.05), respectively, compared to baseline. l -carnitine did not significantly stimulate ketogenesis relative to Control. Per gram tested, butyrate was the most ketogenic, and has the potential to be an ingredient in a ketogenic functional food or beverage.

Background Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits. Objective To determine whether aerobic exercise training modifies brain energy metabolism in mild AD. Methods In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program. Results Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100 g/min; p = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2-3-fold (all p≤0.03). CMRglu was unchanged after Walking (28.0±0.1 μmol/100 g/min; p = 0.96). There was a tendency toward improvement in the Stroop-color naming test (-10% completion time, p = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p≤0.01). Conclusion In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement.

The aim of the present study was to compare the effects of an α-linolenic acid-rich supplement (ALA-RS) on the ketogenic response and plasma long-chain ω-3 polyunsaturated fatty acid in healthy young adults and older individuals.Ten young (25 ± 0.9 y) and 10 older adults (73.1 ± 2.2 y) consumed a flaxseed oil supplement providing 2 g/d of ALA for 4 wk. Plasma ketones, nonesterified fatty acids (NEFA), triacylglycerols, glucose, and insulin were measured over 6 h, before and after supplementation. Total body fat mass was assessed before and after the ALA-RS.The ALA-RS did not significantly modify fasting ketones but postprandial production of β-hydroxybutyrate was increased by 26% (P = 0.037) only in the young adult group. Fasting plasma ketones were positively correlated to fasting plasma NEFA (P 0.01) in both groups. However, the relation was shifted to the right in the older group, suggesting that older adults needed higher plasma NEFA levels to achieve the same ketone amounts as young adults. At baseline, the older group had 47% higher total plasma fatty acids than the young group (P = 0.007). After the ALA-RS, plasma ALA doubled in both groups (P 0.01), an effect that was associated in the older group with a 40% higher eicosapentaenoic acid (EPA; P = 0.004), but no difference in docosahexaenoic acid. The postsupplementation increase in plasma ALA correlated positively with percent total body fat, especially in the older group (r(2) = 0.77; P = 0.0016).In young adults, ALA-RS mildly stimulated postprandial ketogenesis, whereas in the older group, it favored increased plasma ALA and EPA.

Given that aging is associated with higher risk of cognitive decline and dementia, improving early detection of cognitive impairment has become a research and clinical priority. The Montreal Cognitive Assessment (MoCA) is a screening instrument used to assess different aspects of cognition. Despite its widespread use, norms adjusted to the sociodemographics of Quebec-French people are not yet available. Such norms are however important because performance on neuropsychological tests varies according to sociodemographic variables including age, sex, and education. As such, the present study aimed to establish normative data for the MoCA in middle-aged and elderly Quebec-French population.For that purpose, 1,019 community-dwelling older adults aged between 41 and 98 were recruited. Participants from 12 recruiting sites completed the MoCA. Regression-based normative data were produced and cross-validated with a validation sample (n = 200).Regression analyses indicated that older age, lower education level, and male sex were associated with poorer MoCA scores. The best predictive model included age (p .001), education (p .001), sex (p .001), and a quadratic term for education (education X education; p .001). This model explained a significant amount of variance of the MoCA score (p .001, R2 = 0.26). A regression equation to calculate Z scores is presented.This study provides normative data for the MoCA test in the middle-aged and elderly French-Quebec people. These data will facilitate more accurate detection and follow-up of the risk of cognitive impairment in this population, taking into account culture, age, education, and sex.

Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed.

Introduction White matter changes (WMC) in the cholinergic tracts contribute to executive dysfunction in the context of cognitive aging. WMC in the external capsule have been associated with executive dysfunction. The objectives of this study were to: 1) Characterize the lateral cholinergic tracts (LCT) and the superior longitudinal fasciculus (SLF). 2) Evaluate the association between diffusion measures within those tracts and cognitive performance. Methods Neuropsychological testing and high angular resolution diffusion imaging (HARDI) of 34 healthy elderly participants was done, followed by anatomically constrained probabilistic tractography reconstruction robust to crossing fibers. The external capsule was manually segmented on a mean T1 image then merged with an atlas, allowing extraction of the LCT. Diffusion tensor imaging (DTI) and HARDI-based measures were obtained. Results Correlations between diffusion measures in the LCT and the time of completion of Stroop (left LCT radial and medial diffusivity), the Symbol Search score (right LCT apparent fiber density) and the motor part of Trail-B (left LCT axial and radial diffusivity) were observed. Correlations were also found with diffusion measures in the SLF. WMC burden was low, and no correlation was found with diffusion measures or cognitive performance. Discussion DTI and HARDI, with isolation of strategic white matter tracts for cognitive functions, represent complimentary tools to better understand the complex process of brain aging.

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.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.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.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.

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.

Our primary objective in this study was to quantify whole brain and regional cerebral metabolic rates of glucose (CMRg) in young and older adults in order to determine age-normalized reference CMRg values for healthy older adults with normal cognition for age. Our secondary objectives were to--(i) report a broader range of metabolic and endocrine parameters including body fat composition that could form the basis for the concept of a 'metabolic phenotype' in cognitively normal, older adults, and (ii) to assess whether medications commonly used to control blood lipids, blood pressure or thyroxine affect CMRg values in older adults. Cognition assessed by a battery of tests was normal for age and education in both groups. Compared to the young group (25 years old; n = 34), the older group (72 years old; n = 41) had ~14% lower CMRg (μmol/100 g/min) specifically in the frontal cortex, and 18% lower CMRg in the caudate. Lower grey matter volume and cortical thickness was widespread in the older group. These differences in CMRg, grey matter volume and cortical thickness were present in the absence of any known evidence for prodromal Alzheimer's disease (AD). Percent total body fat was positively correlated with CMRg in many brain regions but only in the older group. Before and after controlling for body fat, HOMA2-IR was significantly positively correlated to CMRg in several brain regions in the older group. These data show that compared to a healthy younger adult, the metabolic phenotype of a cognitively-normal 72 year old person includes similar plasma glucose, insulin, cholesterol, triglycerides and TSH, higher hemoglobin A1c and percent body fat, lower CMRg in the superior frontal cortex and caudate, but the same CMRg in the hippocampus and white matter. Age-normalization of cognitive test results is standard practice and we would suggest that regional CMRg in cognitively healthy older adults should also be age-normalized.

Background The cerebral metabolic rate of glucose (CMRg) is lower in specific brain regions in Alzheimer's disease (AD). The ketones, acetoacetate and β-hydroxybutyrate, are the brain's main alternative energy substrates to glucose. Objective To gain insight into brain fuel metabolism in mild AD dementia by determining whether the regional CMR and the rate constant of acetoacetate (CMRa and Ka, respectively) reflect the same metabolic deficit reported for cerebral glucose uptake (CMRg and Kg). Methods Mild AD dementia (Mild AD; n = 10, age 76 y) patients were compared with gender- and age-matched cognitively normal older adults (Controls; n = 29, age 75 y) using a PET/MRI protocol and analyzed with both ROI- and voxel-based methods. Results ROI-based analysis showed 13% lower global CMRg in the gray matter of mild AD dementia versus Controls (34.2 ± 5.0 versus 38.3 ± 4.7 μmol/100 g/min, respectively; p = 0.015), with CMRg and Kg in the parietal cortex, posterior cingulate, and thalamus being the most affected (p ≤ 0.022). Neither global nor regional CMRa or Ka differed between the two groups (all p ≥ 0.188). Voxel-based analysis showed a similar metabolic pattern to ROI-based analysis with seven clusters of significantly lower CMRg in the mild AD dementia group (uncorrected p ≤ 0.005) but with no difference in CMRa. Conclusion Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones.

We automated radiochemical synthesis of 1-[ 11 C]acetoacetate in a commercially available radiochemistry module, TRASIS AllInOne by [ 11 C]carboxylation of the corresponding enolate anion generated in situ from isopropenylacetate and MeLi, and purified by ion-exchange column resins.1-[ 11 C]acetoacetate was synthesized with high radiochemical purity (95%) and specific activity (~ 66.6 GBq/µmol, n = 30) with 35% radiochemical yield, decay corrected to end of synthesis. The total synthesis required ~ 16 min. PET imaging studies were conducted with 1-[ 11 C]acetoacetate in vervet monkeys to validate the radiochemical synthesis. Tissue uptake distribution was similar to that reported in humans.

Introduction Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI. Objective To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD. Methods 24 CTL, 20 MCI and 19 AD of similar age and metabolic phenotype underwent a dual-tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose ( K Glu , CMR Glu ) and acetoacetate ( K AcAc , CMR AcAc ) were evaluated with PET using [ 18 F]-fluorodeoxyglucose ([ 18 F]-FDG), a glucose analogue, and [ 11 C]-acetoacetate ([ 11 C]-AcAc), a ketone PET tracer. Regional brain volume and cortical thickness were evaluated by T1-weighted MRI. Results In AD compared to CTL, CMR Glu was ~ 11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus ( p K Glu was ~ 15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ~ 7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMR AcAc or K AcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was most apparent in temporal and cingulate regions. Discussion This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.

BACKGROUND: Ketones are the brain's main alternative fuel to glucose. Dietary medium-chain triglyceride (MCT) supplements increase plasma ketones, but their ketogenic efficacy relative to coconut oil (CO) is not clear. OBJECTIVE: The aim was to compare the acute ketogenic effects of the following test oils in healthy adults: coconut oil [CO; 3% tricaprylin (C8), 5% tricaprin (C10)], classical MCT oil (C8-C10; 55% C8, 35% C10), C8 (>95% C8), C10 (>95% C10), or CO mixed 50:50 with C8-C10 or C8. METHODS: In a crossover design, 9 participants with mean ± SD ages 34 ± 12 y received two 20-mL doses of the test oils prepared as an emulsion in 250 mL lactose-free skim milk. During the control (CTL) test, participants received only the milk vehicle. The first test dose was taken with breakfast and the second was taken at noon but without lunch. Blood was sampled every 30 min over 8 h for plasma acetoacetate and β-hydroxybutyrate (β-HB) analysis. RESULTS: C8 was the most ketogenic test oil with a day-long mean ± SEM of +295 ± 155 µmol/L above the CTL. C8 alone induced the highest plasma ketones expressed as the areas under the curve (AUCs) for 0–4 and 4–8 h (780 ± 426 µmol ⋅ h/L and 1876 ± 772 µmol ⋅ h/L, respectively); these values were 813% and 870% higher than CTL values (P < 0.01). CO plasma ketones peaked at +200 µmol/L, or 25% of the C8 ketone peak. The acetoacetate-to-β-HB ratio increased 56% more after CO than after C8 after both doses. CONCLUSIONS: In healthy adults, C8 alone had the highest net ketogenic effect over 8 h, but induced only half the increase in the acetoacetate-to-β-HB ratio compared with CO. Optimizing the type of MCT may help in developing ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with aging. This trial was registered at clinicaltrials.gov as NCT 02679222.

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer’s disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

Positron emission tomography using [18F]-fluorodeoxyglucose (PET-FDG) is the primary imaging modality used to measure glucose metabolism in the brain (CMRGlu). CMRGlu has been used as a biomarker of brain aging and neurodegenerative diseases, but the complexity and invasive nature of PET often limits its use in research. There is therefore great interest in developing non-invasive metrics for estimating brain CMRGlu. We therefore investigated resting state fMRI metrics such as regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF) and regional global connectivity (Closeness) with multiple analytical approaches to determine their relationship to CMRGlu. We investigated this relation in two distinct cognitively healthy populations separated by age (27 young adults and 35 older adults). Overall, we found that both regionally and across participants, ReHo strongly correlated with CMRGlu in healthy young and older adults. Moreover, ReHo demonstrated the same age-related differences as CMRGlu throughout all cortical regions, particularly in the default network and frontal areas.

Brain glucose uptake is impaired in Alzheimer’s disease (AD). A key question is whether cognitive decline could be delayed if this defect were at least partly corrected or bypassed. Ketones (or ketone bodies) such as beta-hydroxybutyrate and acetoacetate are the brain’s main alternative fuels. Several studies have shown that in mild-to-moderate AD, brain ketone uptake is similar to that of healthy age-matched controls. Published clinical trials show that increasing ketone availability to the brain via nutritional ketosis has modest benefits on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet or supplements providing medium chain triglycerides. Given the acute dependence of the brain on its energy supply and the ineffectiveness of current therapeutic strategies for AD consideration be given to correcting the underlying problem of deteriorating brain fuel supply during aging.

Ketones (principally β-hydroxybutyrate and acetoacetate (AcAc)) are an important alternative fuel to glucose for the human brain, but their utilisation by the brain remains poorly understood. Our objective was to use positron emission tomography (PET) to assess the impact of diet-induced moderate ketosis on cerebral metabolic rate of acetoacetate (CMRa) and glucose (CMRglc) in healthy adults. Ten participants (35 ± 15 y) received a very high fat ketogenic diet (KD) (4.5:1; lipid:protein plus carbohydrates) for four days. CMRa and CMRglc were quantified by PET before and after the KD with the tracers, 11C-AcAc and 18F-fluorodeoxyglucose (18F-FDG), respectively. During the KD, plasma ketones increased 8-fold ( p = 0.005) while plasma glucose decreased by 24% ( p = 0.005). CMRa increased 6-fold ( p = 0.005), whereas CMRglc decreased by 20% ( p = 0.014) on the KD. Plasma ketones were positively correlated with CMRa (r = 0.93; p

We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer’s disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults

The objective was to determine the effect of long-term dietary supplementation of two types of fish oil on lipid composition and steroidogenesis in adult pig testis. Twenty-four Duroc boars, aged 204.5 ± 9.4 d (body weight 128.1 ± 16.7 kg) received daily 2.5 kg of an iso-caloric basal diet supplemented with: 1) 62 g of hydrogenated animal fat (AF); 2) 60 g of menhaden oil (MO) containing 16% of eicosapentaenoic acid (EPA) and 18% of docosahexaenoic acid (DHA); or 3) 60 g of tuna oil (TO) containing 7% of EPA and 33% of DHA. After these diets were consumed for 7 mo, testicular hormones, phospholipid content, and fatty acid composition of individual phospholipids in testis were determined. Body and reproductive organ weights were not significantly affected by dietary treatments. Testicular tissue from boars fed a TO diet, followed by those receiving MO and AF diets, had the lowest level of phosphatidylethanolamine (TOMOAF; P0.01) but the highest sphingomyelin (TOMOAF; P0.01). For each phospholipid, boars fed either the MO or TO diet had increased total omega-3 fatty acids, particularly DHA (P0.01), by reciprocal replacement of total omega-6 fatty acids (20:4n-6, 22:5n-6). The MO diet increased EPA more than the other diets. Testicular concentrations of testosterone and estradiol were lower in boars fed a TO diet than a MO diet (P0.02). In conclusion, long-term dietary supplementation of fish oil, regardless of the EPA/DHA ratio, modified the fatty acid compositions in testis and affected steroid production of healthy adult boars, which may represent a promising models for future studies on fertility.

Epidemiological studies fairly convincingly suggest that higher intake of fish and omega-3 fatty acids present in fish is associated with reduced risk for age-related cognitive decline (ARCD). Normally, docosahexaenoic acid (DHA) in plasma is positively associated with DHA intake. However, despite being associated with lower fish and DHA intake, unexpectedly, ARCD is not consistently associated with lower plasma DHA. Furthermore, DHA is often slightly but significantly higher in plasma and erythrocytes in the elderly without ARCD compared to young adults. Higher plasma DHA in the elderly may be a sign that their fish or DHA intake is higher but we show here that various aspects of DHA homeostasis also change with age. Our supplementation and tracer studies show that DHA metabolism, e.g. transit through the plasma and apparent retroconversion but not beta-oxidation, is different in healthy elderly compared to healthy young adults. Apolipoprotein E4 increases the risk of ARCD, possibly in part because it changes DHA homeostasis. Therefore, independent of differences in fish intake, changing DHA homeostasis may contribute to making the elderly more susceptible to cognitive decline despite them having similar or sometimes higher plasma DHA than in younger adults.

International audience; Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze.jlr Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety.