The main risk factors for Alzheimer's disease, age and the ∊4 allele of the APOE gene (APOE4), might modify the metabolism of n-3 PUFAs and in turn, their impact on cognition. The aim of this study ...was to investigate the association between dietary fat and plasma concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in elderly persons, taking the APOE4 genotype into account. The sample was composed of 1,135 participants from the Three-City study aged 65 years and over, of whom 19% were APOE4 carriers. Mean plasma proportions of EPA 1.01%, standard deviation (SD) 0.60 and DHA (2.41%, SD 0.81) did not differ according to APOE4. In multivariate models, plasma EPA increased with frequency of fish consumption (P < 0.0001), alcohol intake (P= 0.0006), and female gender (P= 0.02), and decreased with intensive consumption of n-6 oils (P= 0.02). The positive association between fish consumption and plasma DHA was highly significant whatever the APOE genotype (P < 0.0001) but stronger in APOE4 noncarriers than in carriers (P= 0.06 for interaction). Plasma DHA increased significantly with age (P= 0.009) in APOE4 noncarriers only. These findings suggest that dietary habits, gender, and APOE4 genotype should be considered when designing interventions to increase n-3 PUFA blood levels in older people.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The risk of Alzheimer's disease is increased for carriers of apoE4 (E4) or the PPAR-α L162V polymorphism (L162V), but it is decreased in fish and seafood consumers. The link between high fish intake ...and reduced risk of cognitive decline in the elderly appears not to hold in carriers of E4, possibly because better cognition is linked to EPA+DHA in the blood, but only in non-carriers of E4. As yet, no such studies exist in carriers of L162V. Our objective was to determine whether the plasma fatty acid response to a dietary supplement of EPA+DHA was altered in carriers of L162V and/or E4. This was an add-on project; in the original study, men were selected based on whether or not they were carriers of L162V (n 14 per group). E4 status was determined afterwards. All subjects received an EPA+DHA supplement for 6 weeks. L162V polymorphism did not interact with the supplement in a way to alter EPA and DHA incorporation into plasma lipids. However, when the groups were separated based on the presence of E4, baseline EPA and DHA in plasma TAG were 67 and 60 % higher, respectively, in E4 carriers. After the supplementation, there were significant gene x diet interactions in which only non-carriers had increased EPA and DHA in plasma NEFA and TAG, respectively. PUBLICATION ABSTRACT
Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA ...metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8-12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value SUV) 1.75 (interquartile range 1.39-2.57) before to 1.09 (1.04-1.53) after surgery (
= 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (
= 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04-0.31 before to 0.49 (0.20-0.59) SUV after surgery (
= 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (
= -0.79,
= 0.05) and reduced DFA spillover (
= 0.76,
= 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.
Background
An emerging strategy to delay the onset of Alzheimer disease (AD) is to use ketones to overcome the progressive brain energy deficit caused by deteriorating brain glucose metabolism in ...mild cognitive impairment (MCI). Ketones (acetoacetate and beta‐hydroxybutyrate) are the brain’s main alternative fuel to glucose; in contrast to glucose, ketone metabolism by the brain is now known to be unaffected in MCI and AD. Successful brain energy rescue with ketones in MCI was recently reported.
Methods
In the 6‐month, randomized, placebo‐controlled Benefic Trial (NCT02551419), the active arm was a ketogenic medium chain triglyceride (kMCT) supplement in a lactose‐free skim milk emulsion (15 g kMCT twice/day; n = 39 completers). The placebo arm was a non‐ketogenic iso‐energetic vegetable oil (n = 44 completers). Brain ketone and glucose metabolism were assessed by PET.
Results
Performance on all five cognitive domains improved significantly over 6 months in the kMCT group: (i) Episodic memory (trial 1, Free and Cued Recall Test) increased by 1 word (+0.5 Δ Z‐score); (ii) Executive function (Verbal Fluency Test) correct answers increased by 2 words (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), time taken on the Stroop Colour Naming Test decreased by 1 sec (p = 0.09), and errors on the Trail Making Test increased by 0.8 on placebo (p = 0.02); (iii) Language (Boston naming test) correct answers increased by 1.3 words. (iv) Processing speed increased directly with higher brain ketone uptake in several white matter tracts. (v) Improved attention was directly associated with increased ketone uptake and functional connectivity in the dorsal attention network.
Conclusions
Improved cognition correlating positively with improved brain energy supply by ketones suggests a direct link to brain energy status. The moderate effect size of this kMCT intervention indicates a clinically meaningful benefit on certain cognitive outcomes, some of which relate directly to risk of MCI progressing to AD. Other potential ketogenic interventions that have been less well studied in MCI or AD include a ketogenic diet and ketone salts or esters. Whether brain energy rescue with ketones can delay the onset or progression of AD should now be assessed.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Several studies have linked type 2 diabetes (T2D) to an increased risk of developing Alzheimer’s disease (AD). This has led to an interest in using antidiabetic treatments for the ...prevention of AD. However, the underlying mechanisms explaining the relationship between T2D and AD have not been completely elucidated. Objective: Our objective was to examine cerebral 18F-fluorodeoxyglucose (FDG) uptake during normal aging and in AD patients in regions associated with diabetes genetic risk factors expression in order to highlight which genes may serve as potential targets for pharmaceutical intervention. Methods: We calculated regional glucose metabolism differences in units of standardized uptake values (SUVR) for 386 cognitively healthy adults and 335 clinically probable AD patients. We then proceeded to extract gene-expression data from the publicly available Allen Human Brain Atlas (HBA) database. We used the nearest genes to 46 AD- and T2D-associated SNPs previously identified in the literature, and mapped their expression to the same 34 cortical regions in which we calculated SUVRs, to derive. SNPs with a donor consistency of 0.40 or greater were selected for further analysis. We evaluated the associations between SUVR and gene-expression across the brain. Results: Of the 46 risk-factor genes, 15 were found to be significantly correlated with FDG-PET brain metabolism in healthy adults and probable AD patients after correction for multiple comparisons. Using multiple regression, we found that five genes explained a total of 72.5 percent of the SUVR variance across the healthy adult group regions, while four genes explained a total of 79.3 percent of the SUVR variance across the probable AD group regions. There were significant differences in whole-brain SUVR as a function of allele frequencies for two genes. Conclusions: These results highlight the association between risk factor genes for T2D and regional glucose metabolism during both normal aging and in probable AD. Highlighted genes were associated with mitochondrial stability, vascular maintenance, and glucose intolerance. Pharmacological intervention of these pathways has the potential to improve glucose metabolism during normal again as well as in AD patients.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Desaturation of dietary α-linolenic acid (ALA) to omega-3 (n-3) long-chain fatty acids (FAs) is mediated through FA desaturases (FADS1-FADS2) and may be influenced by dietary FA composition.
We ...investigated the effects of diets enriched in flaxseed oil (FXCO) or high-oleic acid canola oil (HOCO) compared with a Western diet (WD) and FADS1-FADS2 single nucleotide polymorphisms (SNPs) on plasma FAs and U-(13)CALA metabolism.
In a randomized crossover design, 36 hyperlipidemic subjects consumed 3 isoenergetic diets enriched in FXCO (20.6 g ALA/d), HOCO (2.4 g ALA/d), or WD (1.3 g ALA/d) for 4 wk. On day 27, blood was sampled 0, 24, and 48 h after the subjects (n = 26) consumed 45 mg U-(13)CALA. The subjects were genotyped for 4 FADS SNPs.
FXCO increased (P < 0.001) plasma ALA, EPA, and docosapentaenoic acid (DPA), with no change in DHA compared with the HOCO or WD diets. At 24 and 48 h, U-(13)CALA recovered as plasma (13)CEPA and (13)CDPA were lower (P < 0.001) after the FXCO diet than after the HOCO and WD diets. No change in (13)CDHA was observed between diets. Minor allele homozygotes of rs174545, rs174583, rs174561, and rs174537 had lower (P < 0.05) plasma EPA, arachidonic acid (AA), EPA/ALA, and AA/linoleic acid compositions and lower (P < 0.05) plasma (13)CEPA enrichment at 24 and 48 h in comparison with carriers of the major allele after all diets. SNPs were not associated with plasma composition of DHA or (13)CDHA enrichment.
An increase in ALA intake resulting in increased plasma EPA composition may be cardioprotective, especially in minor allele homozygotes. This trial was registered at www.clinicaltrials.gov as NCT00927199.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Medium chain triglycerides (MCT) are ketogenic but the relationship between the change in plasma ketones and the change plasma medium chain fatty acids (MCFA)-octanoate, decanoate, or ...dodecanoate-after an oral dose of MCT is not well-known. An 8 h metabolic study day is a suitable model to assess the acute effects on plasma ketones and MCFA after a dose of tricaprylin (C8), tricaprin (C10), trilaurin (C12) or mixed MCT (C8C10).
To assess in healthy humans the relationship between the change in plasma ketones, and octanoate, decanoate and dodecanoate in plasma total lipids during an 8 h metabolic study day in which a first 20 ml dose of the homogenized test oil is taken with breakfast and a second 20 ml dose is taken 4 h later without an accompanying meal.
The change in plasma acetoacetate, β-hydroxybutyrate and total ketones was highest after C8 (0.5 to 3 h post-dose) and was lower during tests in which octanoate was absent or was diluted by C10 in the test oil. The plasma ketone response was also about 2 fold higher without an accompanying meal (
= 0.012). However, except during the pure C10 test, the response of octanoate, decanoate or dodecanoate in plasma total lipids to the test oils was not affected by consuming an accompanying meal. Except with C12, the 4 h area-under-the-curve of plasma β-hydroxybutyrate/acetoacetate was 2-3 fold higher when no meal was consumed (
< 0.04).
C8 was about three times more ketogenic than C10 and about six times more ketogenic than C12 under these acute metabolic test conditions, an effect related to the post-dose increase in octanoate in plasma total lipids.
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
C-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.
Several studies have suggested that glucose hypometabolism may be present in specific brain regions in cognitively normal older adults and could contribute to the risk of subsequent cognitive ...decline. However, certain methodological shortcomings, including a lack of partial volume effect (PVE) correction or insufficient cognitive testing, confound the interpretation of most studies on this topic. We combined (18)Ffluorodeoxyglucose ((18)FFDG) positron emission tomography (PET) and magnetic resonance (MR) imaging to quantify cerebral metabolic rate of glucose (CMRg) as well as cortical volume and thickness in 43 anatomically defined brain regions from a group of cognitively normal younger (25 ± 3 yr old; n = 25) and older adults (71 ± 9 yr old; n = 31). After correcting for PVE, we observed 11-17% lower CMRg in three specific brain regions of the older group: the superior frontal cortex, the caudal middle frontal cortex, and the caudate (P ≤ 0.01 false discovery rate-corrected). In the older group, cortical volumes and cortical thickness were 13-33 and 7-18% lower, respectively, in multiple brain regions (P ≤ 0.01 FDR correction). There were no differences in CMRg between individuals who were or were not prescribed antihypertensive medication. There were no significant correlations between CMRg and cognitive performance or metabolic parameters measured in fasting plasma. We conclude that highly localized glucose hypometabolism and widespread cortical thinning and atrophy can be present in older adults who are cognitively normal, as assessed using age-normed neuropsychological testing measures.
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