Abstract Blood levels of polyunsaturated fatty acids (PUFA) are considered biomarkers of status. Alpha-linolenic acid, ALA, the plant omega-3, is the dietary precursor for the long-chain omega-3 PUFA ...eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Studies in normal healthy adults consuming western diets, which are rich in linoleic acid (LA), show that supplemental ALA raises EPA and DPA status in the blood and in breast milk. However, ALA or EPA dietary supplements have little effect on blood or breast milk DHA levels, whereas consumption of preformed DHA is effective in raising blood DHA levels. Addition of ALA to the diets of formula-fed infants does raise DHA, but no level of ALA tested raises DHA to levels achievable with preformed DHA at intakes similar to typical human milk DHA supply. The DHA status of infants and adults consuming preformed DHA in their diets is, on average, greater than that of people who do not consume DHA. With no other changes in diet, improvement of blood DHA status can be achieved with dietary supplements of preformed DHA, but not with supplementation of ALA, EPA, or other precursors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The primary method for measuring brain metabolism in humans is positron emission tomography (PET) imaging using the tracer
F-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 (r
= 2.83 × 10
, p = 0.67). For non-PVE corrected data age also had the least effect in predicting CMRg in the pons (r
= 3.12 × 10
, 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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Alzheimer's disease (AD) is generally associated with lower omega-3 fatty acid intake from fish but despite numerous studies, it is still unclear whether there are differences in omega-3 fatty acids ...in plasma or brain. In matched plasma and brain samples provided by the Memory and Aging Project, fatty acid profiles were quantified in several plasma lipid classes and in three brain cortical regions. Fatty acid data were expressed as % composition and as concentrations (mg/dL for plasma or mg/g for brain). Differences in plasma fatty acid profiles between AD, mild cognitive impairment (MCI), and those with no cognitive impairment (NCI) were most apparent in the plasma free fatty acids (lower oleic acid isomers and omega-6 fatty acids in AD) and phospholipids (lower omega-3 fatty acids in AD). In brain, % DHA was lower only in phosphatidylserine of mid-frontal cortex and superior temporal cortex in AD compared to NCI (-14% and -12%, respectively; both p < 0.05). The only significant correlation between plasma and brain fatty acids was between % DHA in plasma total lipids and % DHA in phosphatidylethanolamine of the angular gyrus, but only in the NCI group (+0.77, p < 0.05). We conclude that AD is associated with altered plasma status of both DHA and other fatty acids unrelated to DHA, and that the lipid class-dependent nature of these differences reflects a combination of differences in intake and metabolism.
There is considerable interest in the impact of (n-3) long-chain PUFA in mitigating the morbidity and mortality caused by chronic diseases. In 2002, the Institute of Medicine concluded that ...insufficient data were available to define Dietary Reference Intakes (DRI) for eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), noting only that EPA and DHA could contribute up to 10% toward meeting the Adequate Intake for alpha-linolenic acid. Since then, substantial new evidence has emerged supporting the need to reassess this recommendation. Therefore, the Technical Committee on Dietary Lipids of the International Life Sciences Institute North America sponsored a workshop on 4-5 June 2008 to consider whether the body of evidence specific to the major chronic diseases in the United States--coronary heart disease (CHD), cancer, and cognitive decline--had evolved sufficiently to justify reconsideration of DRI for EPA+DHA. The workshop participants arrived at these conclusions: 1) consistent evidence from multiple research paradigms demonstrates a clear, inverse relation between EPA+DHA intake and risk of fatal (and possibly nonfatal) CHD, providing evidence that supports a nutritionally achievable DRI for EPA+DHA between 250 and 500 mg/d; 2) because of the demonstrated low conversion from dietary ALA, protective tissue levels of EPA+DHA can be achieved only through direct consumption of these fatty acids; 3) evidence of beneficial effects of EPA+DHA on cognitive decline are emerging but are not yet sufficient to support an intake level different from that needed to achieve CHD risk reduction; 4) EPA+DHA do not appear to reduce risk for cancer; and 5) there is no evidence that intakes of EPA+DHA in these recommended ranges are harmful.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
•30 g/day of medium chain triglyceride (kMCT) doubles brain ketone metabolism in MCI.•As a result, net brain energy status improved on the kMCT.•Improvement in some cognitive outcomes was positively related to brain ketone uptake.•Both the kMCT and placebo were moderately well tolerated.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
The term ‘essential fatty acid’ is ambiguous and inappropriately inclusive or exclusive of many polyunsaturated fatty acids. When applied most rigidly to linoleate and α-linolenate, this term ...excludes the now well accepted but
conditional dietary need for two long chain polyunsaturates (arachidonate and docosahexaenoate) during infancy. In addition, because of the concomitant absence of dietary α-linolenate, essential fatty acid deficiency is a seriously flawed model that has probably led to significantly overestimating linoleate requirements. Linoleate and α-linolenate are more rapidly β-oxidized and less easily replaced in tissue lipids than the common ‘non-essential’ fatty acids (palmitate, stearate, oleate). Carbon from linoleate and α-linolenate is recycled into palmitate and cholesterol in amounts frequently exceeding that used to make long chain polyunsaturates. These observations represent several problems with the concept of ‘essential fatty acid’, a term that connotes a more protected and important fatty acid than those which can be made endogenously. The metabolism of essential and non-essential fatty acids is clearly much more interconnected than previously understood. Replacing the term ‘essential fatty acid’ by existing but less biased terminology, i.e. polyunsaturates, ω3 or ω6 polyunsaturates, or naming the individual fatty acid(s) in question, would improve clarity and would potentially promote broader exploration of the functional and health attributes of polyunsaturated fatty acids.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Optimal brain performance is intimately linked to the brain’s Yin and the Yang − the balance between its structure and its energy metabolism. This relationship is clearly exemplified in infant brain ...development and in Alzheimer’s disease, and probably also applies to human brain evolution. In these examples,
redundant pathways
help achieve this important balance. For instance, the key structural lipid for the brain, docosahexaenoic acid (DHA), is supplied to the infant brain from at last three overlapping sources: (i) milk; (ii) infant’s own fat stores and (iii) by some endogenous synthesis from α-linolenic acid (ALA) or eicosapentaenoic acid (EPA). On the energy side, glucose is normally the brain’s main fuel but under conditions of prolonged starvation, it can be almost totally replaced by the ketone bodies, acetoacetate and β-hydroxybutyrate. When ketones are present in the blood they spare glucose uptake by the brain because they are actually the brain’s preferred fuel and are essential for normal infant brain development. The redundant sources of ketones are long chain fatty acids (including the relatively ketogenic ALA) in infant stores, and medium chain triglycerides (MCT) in milk. Besides infancy, nowhere is the strain on the brain’s balance between yin and yang more apparent than in Alzheimer’s disease (AD). One of the reasons why attempts to treat AD have largely failed could well be because chronically inadequate glucose supply to some areas of the brain on the order of 10% is present in people at risk of AD long before cognitive decline begins. However, brain ketone uptake is still normal even in moderately advanced AD. Hence, treatments that ignore the brain energy (glucose) deficit in AD would be predicted to fail, but treatments that attempt to rescue brain fuel availability
via
ketones would be predicted to have a better chance of succeeding. By analogy to ketones sparing glucose for brain energy metabolism, perhaps ALA or EPA entering the brain can help spare (conserve) DHA for its structural role. If so, it would not necessarily be futile to transport ALA and EPA into the brain just to β-oxidize the majority afterwards; DHA sparing as well as ketone production could be important beneficiaries.
Les performances optimales du cerveau sont intimement liées au Yin/Yang cérébral : l’équilibre entre sa structure et son métabolisme énergétique. Ce phénomène s’applique spécifiquement au cours du développement cérébral du jeune enfant et de la maladie d’Alzheimer et très probablement tout au long de l’évolution du cerveau humain. Dans le cas des exemples précités, des voies redondantes permettent d’accéder à cet équilibre. Par exemple, le DHA, clé de la structure lipidique cérébrale, est apporté au cerveau de l’enfant
via
au moins trois sources concomitantes : (i) le lait ; (ii) les réserves lipidiques propres à l’enfant ; (iii) enfin,
via
une synthèse endogène à partir de l’acide α-linolénique (ALA) ou de l’acide eicosapentaénoïque (EPA). Sur le plan énergétique, dans des conditions normales, le glucose reste la source principale, mais dans des conditions de jeûne prolongé, il peut être totalement remplacé par l’utilisation de corps cétoniques : l’acétoacétate et le β-hydroxybutyrate. Quand les cétones sont présentes dans la circulation sanguine, elles permettent l’économie de consommation de glucose par le cerveau, car elles représentent le carburant préférentiel et sont alors essentielles pour le développement cérébral normal de l’enfant. Les sources parallèles de cétones sont les acides gras à longues chaînes issus du tissu adipeux de l’enfant (y compris l’ALA qui est modérément cétogène) et les triglycérides à chaînes moyennes (MCT) du lait. Au-delà de l’enfance, l’impact du Yin et Yang dans l’équilibre cérébral n’est nulle-part ailleurs plus évident que dans la maladie d’Alzheimer (AD). Une des raisons pour lesquelles les essais de traitement de l’AD ont tous échoué pourrait être que l’apport insuffisant de glucose dans certaines régions du cerveau (de l’ordre de −10 %) précède le déficit cognitif chez les personnes à risques d’AD. Cependant l’utilisation de cétones par le cerveau est normale, même chez les sujets AD en début de pathologie. Ainsi des traitements qui ne prendraient pas en compte le déficit d’apport énergétique en glucose chez ces sujets sont à risque d’échec, alors que des traitements susceptibles de restaurer l’apport énergétique
via
les cétones ont potentiellement de meilleures chances d’être efficaces. Par analogie aux cétones permettant l’économie de glucose dans le métabolisme énergétique du cerveau, il est possible que l’ALA et l’EPA (qui sont également captés par le cerveau) permettent de préserver la fonction structurelle du DHA. Ainsi, finalement le transport d’ALA et d’EPA vers le cerveau pour être β-oxydés ne serait pas nécessairement un métabolisme futile : il pourrait participer à une économie de DHA et de production de cétones qui en deviendraient les principaux bénéficiaires.
A positive energy balance (energy intake>energy expenditure), in which total fat intake plays an important role, is commonly regarded as a major factor contributing to obesity. Adipose tissue ...development, i.e. both size (hypertrophy) and number (hyperplasia), is stimulated by high dietary fat intake during early postnatal development, a susceptibility that now appears to continue well into adulthood. Recent human and animal studies suggest that by altering rates of adipocyte differentiation and proliferation, differences in the composition of dietary fat may also contribute to adipose tissue development. At least in rodent models, the relative intake of n-6 to n-3 PUFA is clearly emerging as a new factor in this development. In these models, higher linoleate intake raises tissue arachidonic acid, which increases prostacyclin production and, in turn, stimulates signalling pathways implicated in adipogenesis. Signalling pathways stimulated by arachidonic acid probably include phospholipase and/or cyclo-oxygenase activation and may be linked as much to relatively low intake of n-3 PUFA as to excessive dietary linoleate. One factor potentially contributing to oversight about the apparent role of dietary n-6 PUFA (especially excess dietary linoleate) in adipose tissue development is the historical overestimation of linoleate requirements and the enthusiasm for higher intake of ‘essential fatty acids’. More research is needed to address whether disequilibration of dietary PUFA intake contributes to the risk of obesity in humans.
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